In this article, we provide an evidence-based primer of current tools and evolvingconcepts in the area of intraprocedural artificial intelligence (AI) methods incolonoscopy and laparoscopy as a ‘procedure companion’, with specific focus on colorectalcancer recognition and characterisation. These interventions are both likely beneficiariesfrom an impending rapid phase in technical and technological evolution. The domains whereAI is most likely to impact are explored as well as the methodological pitfalls pertainingto AI methods. Such issues include the need for large volumes of data to train AI systems,questions surrounding false positive rates, explainability and interpretability as well asrecent concerns surrounding instabilities in current deep learning (DL) models. The areaof biophysics-inspired models, a potential remedy to some of these pitfalls, is exploredas it could allow our understanding of the fundamental physiological differences betweentissue types to be exploited in real time with the help of computer-assistedinterpretation. Right now, such models can include data collected from dynamicfluorescence imaging in surgery to characterise lesions by their biology reducing thenumber of cases needed to build a reliable and interpretable classification system.Furthermore, instead of focussing on image-by-image analysis, such systems could analysein a continuous fashion, more akin to how we view procedures in real life and makedecisions in a manner more comparable to human decision-making. Synergistical approachescan ensure AI methods usefully embed within practice thus safeguarding against collapse ofthis exciting field of investigation as another ‘boom and bust’ cycle of AI endeavour. It changes the way we work and the skills we need”Alain Dehaze, CEO the Adecco Group Both colonoscopy and laparoscopy are deployed for the diagnosis and treatment ofdisease of the colon and rectum and require high levels of interventionalist cognition anddexterity for the correct, confident labelling of abnormalities encountered in the absenceof hard landmarks. Both interventions provide the opportunity over diagnostic radiology todirectly sample and even cure lesions encountered, ideally at the index procedure. To do sorequires real-time human realisation of abnormality and a qualitative decision based ontraining and experience to act as part of the perception/action neural loop in theinterventionalist’s brain. Surgical decision-making is particularly rooted in the opinionand judgement of the human expert with less objective visual aids to prompt or justifyactions than those available to the endoscopist.Minimal access interventions provide screen-based display of internal appearances for humanpractitioner interpretation to guide intellectual and mechanical progress through a complexprocedure. Since its inception in the 1960s, such videoscopy has revolutionised our abilityto diagnose, monitor and manage an abundance of gastrointestinal conditions at sitesotherwise inaccessible without traditional operation.4) or through procedural organisation . Challenges remain though as both colonoscopy and laparoscopy are fundamentallyoperator-dependent procedures. This is compounded by patients with colorectal disease whoultimately require specialist input presenting to a variety of healthcare settings bothelectively and emergently, and so their initial care is via a spectrum of practitioners withdiffering levels of expertise and technological capability. Artificial intelligence (AI)methods offer the opportunity to augment human interpretation intraprocedurally and toprovide statistical measures of the relevance of lesions as they are encountered in realtime, including all contributory data around the case (e.g. pathology and radiology). Logically, these can progress to decision support systems for critical steps whetherremoval, in situ ablation or accelerated, streamlined further investigation to ensure theright patient gets exactly the right level of care improving interventional accuracy andminimising wasteful over-investigation. Modern-day computer vision (CV) techniques offerseveral potential benefits to a surgeon , whereby an AI system can be programmed to learn from exampledata (and not decision rules) to perform classification and prediction tasks, marked abreak from traditional knowledge-based approaches. DL then evolved in the mid-2010s.Increased computing capabilities and algorithmic advances, for example, back propagation,meant learning algorithms consisting of many networked layers of interconnected processingunits known as neurons could be designed as neural networks ((NNs), first conceived in the1940s), in principle, similar to human NN whereby inputted data are passed through severalcomplex hidden steps to extract patterns from data at scale arriving at an output.Inclusion of a mathematical operation called convolution, a specialised kind of linearoperation, in place of general matrix multiplication in at least one layer of a NN opensDL application to visual imagery in the form of a convolutional neural network (CNN).The 1990s saw a resurgence in AI research with advancements so significant that thisperiod is now referred to as the ‘first AI revolution’ with standout examples of computerssurpassing even brilliant human minds in specific tasks (e.g. IBM’s Deep Blue defeat ofchess Grand Master Garry Kasparov).13 Deep learning howeverrequires a large corpus of examples (commonly tens of thousands of examples) for trainingand testing. The ground breaking DeepMind project in ophthalmology required one millionretinal scans to achieve its results. This requirement limits the application of DL to all, but the most commonprocedures where archives of large numbers exist from routine application. Techniques toreduce the dependence of learning algorithms on large volumes of data are an active areaof research in the ML community.The use of DL is growing rapidly across many areas of medicine. Specific DL architecturessuch as CNNs have successfully performed image recognition tasks such as detection ofdiabetic retinopathy and cutaneous melanoma and the classification of breastlesions. Simplifying the description of complex biophysical processes of interest in thisway can help develop accurate predictive techniques, with confidence intervals, withoutdependence on vast image banks. Recent studies of angiogenesis demonstrate how afundamental understanding of cell biology, gained through traditional experimental models,can be combined with mathematical/computational modelling to explore the spatial andtemporal aspects of vessel replication in new ways.Other methods of AI exist, for example, specific mathematical modelling techniques suchas biophysics-inspired modelling (BIM) which builds on understanding of the dynamics ofbiological and physical processes to describe them in terms of a simplified number ofparameters. For instance, perfusion of blood through tissue is well described in theliterature using a range of so-called compartment models which reduce the complexunderlying advection and diffusion processes into a small number of physical parameters.AI methods so can likely play a role in assisting interventionalist orientation viacontinuous re-evaluation of the procedural field in real time to draw the operator’sattention to the important clinical regions and help cancel out unhelpful surroundingnoise. While the endoscopist and surgeon are generally performing a similar visuallydriven act, the spectrum of signals and potential actions precipitated is much broader forthe surgeon. Arguably therefore the role of colonoscopy in the detection, characterisation andresection of these lesions is more valuable than its role in diagnosing cancer andunderpins its worldwide adoption. 1% increases in adenoma detection rates (ADRs) atcolonoscopy have shown 3-6% reductions in interval cancer rates.18 However ADRs vary greatly betweeninstitutions for numerous reasons including endoscopist experience, withdrawal time andthe number of individuals observing the monitor during procedures.20 While imaging quality advances such asnarrow band imaging (NBI) and chromoendoscopy, as well as regular auditing of keyperformance indicators have improved standards worldwide, these measures areinconsistently implemented between centres. Along with detection, lesion/tissue characterisation is an essential attribute ofeffective colonoscopy. While it remains important to detect and adequately resect allsessile serrated or adenomatous polyps, there exist many diminutive non-neoplasticpolyps, especially in the rectosigmoid region, that are of no clinicalrelevance.22 The removal of theselesions places a large burden on histopathology services as well as putting patients atrisk of undue harm from unnecessary polypectomy. Aside from leaving innocuous lesions,confidence in the correct categorisation of lesions that do need address accelerates thepatient towards definitive care.Studies have consistently proven that adenomatous polyps represent potentiallycancerous precursor lesions and that their removal is positively associated with reducedcolorectal cancer rates.24 Robotic-assisted systems provideelectromechanical platforms that enable greater precision at instrument tips. Neithermethod has yet augmented intraoperative decision-making other than providing improvedvisualisation. Therefore, safe and effective surgery depends crucially on the surgeon’sability to recognise structures in the field of vision and to plot the operativesequence from initiation through to conclusion. Similar to colonoscopy and different toother surgical fields such as orthopaedics, there is a lack of rigid measures oforientation and therefore, it is difficult to provide means of anatomical direction andmile-stoning other than via surgeon expertise with continuous checking to reassure.Inter-individual variation, prior surgery, disease and obesity can challenge anatomicalrecognition including fascial plane, neurological structure and adjacent organidentification.In the last 20 years, much elective operation for colorectal cancer is now commencedand completed laparoscopically. The advantages to this approach are well proven in termsof short-term convalescence, and it is now the standard access of choice. Frozen section provides a degree of intraprocedural assistance to the operator incertain circumstances; however, it is not always available and may not be definitivewith small, fragile tissue samples. Similar so to colonoscopy, an ability to detect andcharacterise lesions and recognise major normal anatomy automatically is crucial,especially in high stakes decision-making during major operation where it needs to berapid and highly accurate. However, the field of view is more complex.In particular, classification of lesions unrecognised by preoperative imaging and seenfor the first time at surgery currently relies on the subjective assessment of theoperator. The peritoneum along with the mesocolonic, mesenteric and liver surfaces isoften poorly characterised on computerised tomographic imaging, yet any lesions presenthere affect the staging of the patients and impact theranostically.27 Early exploits involved rudimentary AImethods performing retrospective analysis of initially static, followed by dynamic,images.31 These methods providedacceptable sensitivities and specificities in post hoc static image testing that then fellsharply when attempts were made at real-time analysis.34 Furthermore, the desire to ensuredetection of all lesions encountered came at the price of unacceptably high false positive rates. The emergence of big data and CNNs saw the resurgence of AI methods in endoscopy aswell as near real-time decision-making and reduced false positive rates.38As a commonly performed procedure readily suitable to image capture, AI methods havedeveloped in endoscopy and are now commercially available  concentrated predominantly in the areas of lesion detection andcharacterisation and, more recently, are providing assistance in quality measures such asbowel preparation and withdrawal times.Wang et al. recently published on 1058 patients randomised to either standard or computer aidedcolonoscopy with a significant increase in adenoma detection per patient being seen . Even more impressively, Su et al. reported data from a randomised study of 623 patients whereby 315 patients wereallocated to conventional, unassisted colonoscopy and 308 patients assigned to theirautomatic quality control system (AQCS). This system incorporated 5 Deep CNN models toautomatically time scope withdrawal (triggered by the systems recognition of the caecum),detect polyps (adenomatous and non-adenomatous) as well as assessing bowel preparationdynamically after system training on data from 4000 patients with white light imageslabelled by two gastrointestinal experts. This is the first time that AI methods monitoredsuch important quality measures with the user being prompted to suction debris or slowdown withdrawal rate when appropriate. Fundamentally, this approach represents a shiftaway from unidimensional structure (polyp) recognition to a computer system acting as atype of ‘procedure companion’ that accompanies the operator and provides active guidancethroughout the journey. The authors reported statistically significant increased rates oftotal polyp (.383 vs .254) as well as adenoma (.289 vs .165) detection rates in their AQCSstudy arm as well as significantly increased scope withdrawal times (7.03 vs5.68 minutes). False prompt rates of .21 prompts per colonoscopy were reported in thisstudy. As is a common feature throughout AI methods for polyp detection false positivesremain a challenging aspect for AI methods to overcome. Hassan et al. intheir report quote ‘negligible false positive rates’ of .9% false positive frames in theirfirst validation study. They also acknowledge however that real-life data will consist ofroughly 50,000 frames per colonoscopy suggesting that this false positive frame rate willlikely remain notable in clinical practice.As is the natural progression in emerging technologies, small pilot studies have pavedthe way for larger randomised trials.  Increasing the contrast in the field of view, especially as it may relate toeither critical structure normal anatomy (for preservation) or disease identification, as has been seen in the field of fluorescence-guided surgery (FGS) isideal terrain for CV application.43 This combines extended spectralimaging with exogenous fluorophore administration (predominantly indocyanine green –(ICG)46 to discloseinformation regarding the nature of the tissues being seen by the visualisable presenceof contrast dye in the region of interest such as perfusion characterisation or biliaryanatomy identification (ICG circulates in the blood stream before being excretedunchanged in the bile). Ureters have been similarly visualised using methylene blue (an agent excretedselectively by the kidneys) and a shorter wavelength illumination (c700 nm vs 780 forICG) although progress to routine clinical use is being held up due to licencing issuesrelated to the agent. There are many additional agents in development and some even in phase 2 clinicaltrials that aim to further advance the field in terms of structure specificity and easeof identification.AI in surgery is not at all as advanced as in colonoscopy. This is likely due to theincreased complexity and heterogeneity of structures and elements in any field of viewcombined with the general lack of similar annotated video banks for exploitation. Whereit does exist, it is currently deployed for operative video segmentation and provisionof crude measures of operative fluency such as measuring the time the camera is in theinterior, instrument profiling and partitioning of an operation into its major steps.With such added contrast, AI has a promising role to play in providing means ofobjectively quantifying dye presence, especially if needed to do so kinetically, thatis, determine the rate of filling or emptying of contrast from the region of interest.This would potentially add much information and ease use of many agents which right noware predicated upon administration long before surgery in order to aid humanidentification . By trying to create a static, colouredfield, the techniques of FGS are prone to false positives and error especially if thetiming is different to what had originally been planned (operative lists are variable interms of exact procedure times). Usefulness is limited however if agents must bepre-planned and administered days before surgery rather than being used simply at thepoint of necessary enquiry. Furthermore, because much information is known regarding dyeand illumination energy behaviour in tissue, this can be factored into AI algorithms byexploiting BIM to characterise the underlying video signal in terms of well-knownphysical parameters related to diffusion and advection. A particular attraction of thebiophysics-inspired approach is that it alleviates the requirements for millions ofimages in the training bank as is typical in pure ML or DL approaches. This method thendoes not rely on the analysis and comparison of surface appearance alone but insteadseeks to delve into the very biology of the tissue in question. In the realm offluorescent-guided surgery, AI sensitivity may allow less specificity in agentdevelopment as the fluorescent agent will no longer have to do all the work in lesionidentification (nor indeed will the human in its recognition).51The ability to characterise lesions based on their biology dramatically reduces thenumber of cases needed to build a reliable system and instead of focussing on image byimage analysis could analyse in a continuous fashion, more akin to how we view theprocedures in real life. Furthermore, identification of tissue based on its truebiology, rather than on attempted identification by patterns such as shape or colour asused in the DL methods seen in endoscopy, will address the still present issue of falsepositives. We have already proved this concept in primary colorectal cancer usingcomputer-aided interpretation of minute differences in dynamic perfusion patternsbetween the distorted architecture of neoplastic tissue and that of the surrounding‘normal’ tissue. Our experimental study of this BIM on a corpus of 20 colorectal cancerendoscopic videos correctly identified 19/20 (95%) lesions with 100% cancer sensitivity(91.7% specificity).13 The advent of DL/NN has improvedresearch results for colorectal lesion characterisation and detection; however, thesesystems fundamentally rely on large banks of reference images from which they ‘learn’. Toincrease system performance, more training images need to be acquired. Such ‘polyp maps’are created through analysis of, in some cases, millions of images to detect new similarappearing lesions among images previously unseen to the system with studies using‘in-house’ databases of reference images. This limits comparison of results across studiesundermining generalizability. Also, the need for large volumes of images increasinglypresents moral challenges as well as logistical ones. These concerns relate to dataownership and patient privacy, particularly in the cases of ‘for profit’ systems. The‘black box’ nature of these complex systems may also understandably raise similarconcerns. In many cases, the exact workings of these systems remain incompletelyunderstood yet are earmarked for widespread use in the delivery of modern healthcare inthe near future. In the early stages of clinical integration, the concept of‘explainability’ of results generated from such systems is a crucial component of adoptionby healthcare providers and insurers. This differs from ‘interpretability’ which relatesto the extent to which a cause and effect can be observed within a system. Furthermore,Antun et al. recently highlighted the inherent instability of DLbecause of the processes it uses to reconstruct and store images. Imperfect image reconstruction methods that are accentuated with increasing volumesof images collected may lead to computational errors.Artificial intelligence methods promise to significantly boost human decision-making interms of image recognition and are already making inroads into soft tissue endoscopymoving beyond rigid object (like that seen with self-driving cars) and defined margin(that used for melanoma photographs and mammograms) analysis.In contrast, BIM has the advantage over other AI techniques when it comes to‘interpretability’. Their decision processes build their foundation upon known biologicalphenomena which results in a more predictable pattern of decision-making and more closelyreplicates the human minds decision processes. For decisions in surgery and evenendoscopy, especially where dynamic modelling of tissues may be helpful, the use offluorescence and computer-aided decision augmentation may help to smooth the differencesin operator ability from centre to centre using computer classifiers that are easilyinterpreted to assist the operator in their endeavours to provide the highest level ofcare to patients. Furthermore, computer processes could provide alternative presentationof data through mathematical modelling such as 2D and even 3D maps of the tumour. Such AIsystems that analyse in real time based on tissue biology also obviate the need for thecollection of large masses of patient data for training purposes and, if successful, wouldhave implications across all disciplines of healthcare. Furthermore, such in vivo contrastenhancement can help train AI systems on the corresponding white light imagery.While the era of AI and computer augmented decision-making in medicine is still very muchin its infancy, it likely portends a significant revolution in improving the standard ofhealthcare delivered worldwide, and it is developing rapidly. The increasingly widespreadavailability of technology allows more research groups than ever access to this rapidlyevolving area and thus further promotes improvements. Daunting barriers to use on a largescale remain, however, most notably the high rate of false positives, the large volumes ofcomparative pictures that are currently required to ‘educate’ these computer systems and thedifficulties associated with explaining and accounting for unseen, and poorly understood,processes happening within some AI models. Correct clinical integration also needsconsideration likely in the first phases as collaborative systems rather than challengingthe role of the doctor as decision-maker with the likely advent of a new type ofpractitioner, the interventionalist .Importantly too, the history of computer science teaches us that, whatever the AImethodology, always unforeseen pitfalls arise leading to ‘boom and bust’ cycles furtherencouraging complementary methods of advance to safeguard against collapse of this excitingfield of investigation.


Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and represents a heterogeneous disorder with a complex pathological basis. While significant technological advances have taken place over the last decade in the field of catheter ablation of AF, response to ablation varies and long-term success rates in those with persistent AF remain modest. Mechanistic studies have highlighted potentially different sustaining factors for AF in the persistent AF population with substrate-driven focal and re-entrant sources in the body of the atria identified on invasive and non-invasive mapping studies. Translation to clinical practice, however, remains challenging and the application of such mapping techniques to clinical ablation has yet to demonstrate a significant benefit beyond pulmonary vein isolation (PVI) alone in the persistent AF cohort. Recent advances in catheter and ablation technology have centered on improving the durability of ablation lesions at index procedure and although encouraging results have been demonstrated with early studies, large-scale trials are awaited. Further meaningful improvement in clinical outcomes in the persistent AF population requires ongoing advancement in the understanding of AF mechanisms, coupled with continuing progress in catheter technology capable of delivering durable transmural lesions. Atrial fibrillation (AF) represents the most common cardiac arrhythmia worldwide and is associated with a significant burden of morbidity and mortality. The incidence of AF has increased dramatically over the last two decades and current prevalence is expected to further double between 2010 and 2060 with a predicted 17.9 million adults living with AF by this timepoint , outcomeThe observation by Haissaguerre et al. nearly two decades ago that AF may be initiated by focal pulmonary vein triggers led to the development of the pulmonary vein isolation (PVI) radiofrequency (RF) ablation procedure, the endpoint of which is electrical disconnection of the pulmonary veins . PVI repAlthough the majority of studies evaluating the technique of PVI, evolving from targeted ablation of ectopy within the pulmonary veins to wide area circumferential ablation, focused on paroxysmal AF patients, several assessed this approach in persistent AF patients. An early study of segmental isolation of the pulmonary veins including a small number of persistent AF patients demonstrated significantly lower success rates at one year compared to those with paroxysmal AF, with over 50% experiencing recurrence . AlthougThe inferior results seen with PVI alone in the persistent AF cohort are likely to reflect substrate-driven AF, in the setting of more advanced atrial remodeling, as distinct from trigger-driven AF in early paroxysmal AF which responds well to PVI. Conduction velocity heterogeneity and altered tissue refractoriness consequent on progressive atrial fibrosis and dilatation increase vulnerability to the development and maintenance of AF ,15,16,17The motivation for left atrial linear ablation was based on experience with the surgical maze procedure involving atrial compartmentalization through the creation of lines of electrical block, theoretically reducing the ability of the atria to sustain re-entry circuits responsible for AF maintenance .The Bordeaux group first described the technique of linear ablation at the mitral isthmus and the left atrial roof as an adjunct to PVI in 2004 , the endA linear ablation strategy of ‘box isolation’ of the posterior left atrial wall, consisting of a roof and an inferior transverse line joining the encircled pulmonary veins was described by Kumagai et al. in 2007  with theDistinct from endpoint driven PVI and linear ablation, the ablation of complex fractionated atrial electrograms (CFAE) represents a strategy that gained significant traction over the last two decades. CFAEs can be defined as electrograms displaying continuous electrical activity, short mean cycle lengths or complex fractionated potentials . The jusA ‘stepwise’ approach for ablation combining CFAE and linear ablation in persistent AF patients was first described by Haissaguerre et al. in 2005 ,51. Thisp = 0.015) again underscoring the modest results obtainable in this patient group. This study did not evaluate the stepwise approach, however, and in those receiving linear ablation as an adjunct strategy block across both lines was achieved in only 74% of patients.The multicentre STAR AF II trial published in 2015 represents the most robust evaluation of ablation strategy in persistent AF patients to date . In thisDespite the abundance of studies evaluating different ablation techniques in the persistent AF population, there remains a lack of consensus regarding the optimum strategy in this cohort and a strong suggestion from STAR AF II that ablation beyond PVI may not be of benefit. As such, the central role of PVI is underscored in the 2020 ESC guidelines while the employment of additional lesions beyond PVI may be considered but are ‘not well established’ and carry a class IIb recommendation [In parallel with the evaluation of different ablation techniques, a drive towards a better understanding of AF mechanisms resulted in the emergence of two major invasive and non-invasive forms of AF mapping technology, namely ‘Focal impulse and rotor modulation’ or FIRM mapping and electrocardiographic imaging or ECGi mapping. These techniques employ the principle of phase mapping, a mathematical approach for the assessment of spatial and temporal periodicity in tissue and identification of periodic rotations or ‘rotors’ . In mechp < 0.001). These results were maintained at three years [p = 0.96) [FIRM mapping is an invasive endocardial phase mapping technique that utilizes a custom-made, 64 pole basket contact catheter  covering at least 80–90% of the atria to map AF. AF propagation maps, generated from monophasic action potentials and processed using specialized software, are used to guide intra-procedural elimination of sources demonstrating appropriate spatial and temporal stability . The CONee years  leading ee years ,59. Furt = 0.96) .Electrocardiographic imaging mapping or ECGi mapping is a non-invasive phase mapping approach that utilizes a 252 body-surface electrode array combined with thoracic imaging to display virtual cardiac potentials on the epicardial surface . Re-entrInherent limitations of these mapping techniques relate to electrode density and mapping resolution as well as the potential for poor electrode contact in the case of invasive FIRM mapping. Transformation of electrograms using phase mapping is a complex process, and an obvious disadvantage is a limited ability for raw signal analysis by the operator prior to transformation. This, coupled with conflicting results regarding driver stability using FIRM vs. ECGi mapping has fueled skepticism about reproducibility and validity. In recent years, further systems have been developed to facilitate mapping of focal and rotational activity without the need for phase mapping transformation including the Cartofinder (Biosense Webster) contact mapping system and the AcQMap  non-contact ultrasound-based mapping system. These platforms are capable of identifying focal and rotational activation during AF with the elimination of such activity associated with high procedural AF termination and midterm success rates of up to 72% in persistent AF patients ,66. As fTaken together, the aforementioned studies do not suggest a significant incremental benefit of an adjunct ablation strategy targeting rotors or drivers, with arrhythmia-free survival similar to a conventional ablation approach. Further development in mapping technology and standardization of electrogram analysis is needed to facilitate ongoing understanding of AF mechanisms that can be translated into a meaningful clinical benefit to the patient.Returning to the central message of STAR AF II, and considering the overall modest results reported with mechanistic mapping techniques, in recent years focus has been placed on the biophysics of ablation and the durability of ablation lesions. Although the inferior results seen in persistent AF ablation may be explained by an incomplete understanding of AF mechanisms, another possible explanation is a failure to achieve durable transmural ablation lesions at index procedure. Certainly, prior to the introduction of contact force sensing catheters, rates of pulmonary vein reconnection at repeat procedure were reported as high as 94%  while siThe Ablation Index  is a real-time lesion assessment index incorporating force, time, and power in a weighted formula. Ablation Index has been shown in canine studies to predict lesion depth  and in hAside from PVI, novel RF delivery protocols have been employed for, and shown benefit in, additional substrate ablation in patients with persistent AF. The ALINE study examined the effect of optimized, contiguous RF lesion delivery  on the rate of first-pass block of linear ablation at the left atrial roof and mitral isthmus in 41 patients with persistent AF. A high rate of first-pass block at the roof (93%) but not the mitral line (23%) was reported using this protocol  Figure . AdditioIndeed, the complex anatomy of the mitral isthmus often necessitates additional epicardial ablation within the coronary sinus in order to achieve block. Ethanol infusion of the Vein of Marshall was proposed as an adjunct to RF ablation with several studies confirming its added value for achieving block along the mitral isthmus . A 2020 p = 0.325) albeit with lower procedure and fluoroscopy times in those undergoing the voltage guided approach [Invasive assessment of atrial bipolar voltage has gained significant attention over the last number of years, with left atrial scarring, defined as a bipolar voltage of <0.05 mV in sinus rhythm, identified as a powerful independent predictor of AF recurrence post ablation . In receapproach . EndpoinIn the last decade, cryoablation, the ‘single-shot’ technique of isolating the pulmonary veins using a cryoballoon cooled to approximately −40 °C has emerged as an alternative catheter ablation strategy in patients with AF . Its nonGiven the variable success rates reported in prior studies of ablation outcome, it is important to consider the methods employed for post-procedural rhythm monitoring when interpreting results. The intensity of rhythm monitoring on follow-up has been demonstrated in multiple studies to be associated with greater sensitivity and specificity for the detection of arrhythmia recurrence . This isAlthough procedural success has been traditionally defined as freedom from ≥30 s of atrial tachyarrhythmia, the CLOSE to CURE study evaluating ‘CLOSE’ protocol guided ablation utilized the novel outcome measure of atrial tachyarrhythmia burden on implantable cardiac monitoring. In this study, a 100% reduction in arrhythmia burden was demonstrated on follow-up . This reThe broad spectrum of atrial remodeling encompassed by the term persistent AF suggests that ‘patient-tailored’ ablation may be a more appropriate strategy than ‘one size fits all’ ablation in this cohort. In our centre, therefore, we undertake a workflow for first-time persistent AF ablation that is guided by AF burden on continuous long-term monitoring and the presence of risk factors for non-PV triggered AF. Those with self-terminating AF and no features of advanced atrial remodeling are deemed to have ‘pseudo’ persistent AF and undergo PVI alone as per the CLOSE protocol . PatientHigh power–short duration ablation is a novel technique that offers a theoretical advantage due to a reduction in the time-dependent conductive heating phase of lesion formation with less consequent collateral tissue damage . In swinOne of the most exciting developments in ablation delivery in recent years is that of pulsed field ablation (PFA), a non-thermal ablative technique that causes cell death through the destabilization of cell membranes. Its potential advantage over RF lies in the preferential targeting of myocardial tissue with a reduction in collateral tissue damage demonstrated in pre-clinical studies ,97,98. TPatients with persistent AF remain a particularly challenging cohort with conflicting evidence regarding the optimal catheter ablation strategy in these patients. Progressive atrial remodeling beyond the pulmonary veins results in substrate-driven AF that is likely to be mechanistically different from that seen in paroxysmal disease, with further significant variation in the degree of remodeling within the persistent AF cohort itself. Despite the wealth of published data on adjunctive substrate-based ablation for persistent AF, no technique has demonstrated a consistent benefit over PVI alone, and latest guidelines underscore the central role of PVI in all patient populations. Advances in catheter technology coupled with optimized, parameter-driven ablation workflows have translated into increased PVI durability on follow-up in recent years, with novel methods for energy delivery demonstrating further potential for improving ablation efficacy and safety. This progress coupled with ongoing research into AF mechanisms and advanced substrate assessment will be central to the refinement of ablation strategy on a more individualized basis and the improvement of outcomes in this population.


Denver Child Study for a sample of approximately 590 Latino and African American children and youth whose families were quasi-randomly assigned to subsidized housing operated by the Denver (CO) Housing Authority during part of their childhood. We employed binary response models with endogenous explanatory variables, estimated using instrumental variables (IV) probit and average marginal effects to identify predictors of a neurodevelopmental disorder diagnosis during childhood. We found that multiple dimensions of neighborhood context—especially neighborhood socioeconomic status, older housing stock, residential instability and prevalence of neurological hazards in the ambient air—strongly and robustly predicted the diagnosis of a neurodevelopmental disorder during childhood.Nearly three out of ten neurodevelopmental disabilities in the United States have been linked to environmental conditions, prompting emerging lines of research examining the role of the neighborhood on children’s developmental outcomes. Utilizing data from a natural experiment in Denver, this study quantifies the impact of exposure to varied neighborhood contexts on the diagnosis of neurodevelopmental disorders over the course of childhood. Our analysis is based upon retrospective child, caregiver, household and neighborhood data derived from the  Since the National Research Council of the United States reported in 2000 that more than 28% of neurodevelopmental disabilities have an environmental origin, why some children have inferior developmental outcomes has been the subject of heightened scholarly study and debate. Though heritable and household contextual factors are undoubtedly vital, some argue that both physical  and social  dimensions of the environment—the oft-labeled “neighborhood effects” literature—generate impacts ,2. This Neighborhoods may affect children’s development through a variety of causal mechanisms operating either through social, institutional or biological processes; for extended discussions see Sampson, Morenoff and Gannon-Rowley  and GalsSeveral multivariate statistical studies based on individual observations, and adjusted for relevant individual and parental characteristics, have explored the association between aspects of neighborhood physical, social and demographic environment  and children’s various neurodevelopmental disorders and cognitive outcomes. Numerous studies have documented statistical associations between such outcomes and concentrations of neurotoxins in the environment. Key neurotoxins investigated have been various particulate matter components of air pollution ,25,26, lAnother substantial body of research has identified associations between children’s poorer cognitive outcomes and the low socioeconomic position of their neighborhoods ,49,50,51The causal interpretation of the associations measured by these studies is, however, clouded by the geographic selection bias problem; for methodological reviews, see Sampson, Morenoff and Gannon-Rowley  and GalsIn a random-assignment experiment, data are produced by an experimental design whereby households are randomly assigned to different neighborhoods. The only extant example of a random assignment experiment relevant to the health field is the well-known Moving To Opportunity (MTO) demonstration project . The MTOIn natural quasi-experiments, observations are produced by idiosyncratic housing policy interventions, such as subsidized housing desegregation or revitalization programs, or inclusionary zoning regulations, which create exogenous variation in neighborhood environments for assisted tenants . AlthougThe current study represents the first such approach in this field. Our study hopes to contribute by leveraging a natural quasi-experiment associated with the Housing Authority of the City and County of Denver (DHA). In this paper we quantify the impact of exposure to varied neighborhood contexts on the diagnosis of neurodevelopmental disorders  or attention deficit hyperactivity disorder (ADHD)) for low-income Latino and African American children. Specifically, we address the following research question:For Latino and African American children who spent at least two years of their childhood living in subsidized housing, are there statistically and substantively significant differences in the diagnosis of neurodevelopmental disorders attributable to differences in their childhood neighborhood socioeconomic, demographic, safety and physical environments, all else equal?Our work advances the literature on quantifying the neighborhood’s causal impact on low-income, minority children’s development in two ways. First, because caregivers of our sampled children were quasi-randomly assigned to neighborhoods, the challenge of parental geographic selection bias is addressed. Second, we evaluate an unprecedented variety of measures of neighborhood environment , measured at different spatial scales, which vary substantially across the sample.In addition to its 3000 units in large-scale, conventional public housing developments, the DHA has operated since 1969 a dispersed housing program providing approximately 1500 low-income families with opportunities to live in scattered-site, single-family and small-scale, multi-family units. These dispersed units are located in a wide range of neighborhoods throughout the congruent City and County of Denver, whereas the conventional developments are typically more concentrated. From 1987 to 2005, as applicants came to the top of the public housing waitlist, they were offered a vacant DHA unit with the number of bedrooms appropriate for their family size and gender of children. If offered units were refused, applicants were dropped to the bottom of the waitlist. As detailed in Santiago and colleagues , we haveAnother important feature of our natural experiment is the comparatively long exposures children in DHA families had to their assigned neighborhoods. Our study sample had a 6-year mean (median = 5 years) duration in DHA subsidized housing, approximately twice as long as reported for the MTO experimental group . Previous work by Wodtke, Harding and Elwert  and CrowOur analytical approach for causal identification exploits the quasi-experimental assignment that produces exogenous variation in neighborhood context. Specifically, the “treatment” that the DHA offers to its families is a complex bundle of neighborhood attributes (the components of which we describe below). We test the consequences of these various treatments by employing binary response models with endogenous explanatory variables, estimated using instrumental variables (IV) probit to calculate the average marginal effects of neighborhood attributes on the probability of ever being diagnosed with a neurodevelopmental disorder during childhood. We only consider children’s initial diagnoses occurring after their families have been quasi-randomly assigned to a DHA public housing unit, thereby preserving the value of the natural experiment for drawing causal inferences. First-offer neighborhood characteristics are used as instruments for estimating neighborhood characteristics at time of initial diagnosis.Our analytic approach shares much in common with the MTO study. Low-income families are (quasi-) randomly assigned to different neighborhood contexts and are then permitted to move as they wish. In the case of the MTO experimental group, such moves occurred after a minimum one-year stay in a low-poverty area. Several years later, researchers retrospectively analyze whether children exposed to these different contexts behaved differently, controlling for characteristics of their families. As in MTO, we do not view potential residential moves from the originally assigned DHA dwelling as a source of geographic selection bias, but rather as a potential impact of the original treatment.Denver Child Study, a retrospective study of Latino and African American, current or former Denver (CO) Housing Authority (DHA) residents whose families were randomly assigned to subsidized housing units and neighborhoods during the period between 1987 and 2005  whether the child, by the time of our survey (or by 18 if this age or older at time of survey), had been clinically diagnosed with one or more neurodevelopmental disorders: mental retardation or intellectual disabilities, learning disabilities, developmental delays, autism, ADD or ADHD; and (2) the child’s age at time of diagnosis or time of survey or age 18 if not diagnosed. Approximately 7% of our sampled children were diagnosed with neurodevelopmental disorders since moving into DHA, with a mean age of diagnosis at 6.5 years (range 2–14 years); see In the We recognize that there is ambiguity in our neurodevelopmental disorder indicator, as is the case in most community health investigations. A diagnosis outcome results from the joint probabilities that a child exhibits adverse health symptoms, and that the caregiver will seek medical advice given the symptoms. The latter probability, in turn, is a function of the caregiver’s physical and mental health, personal efficacy, economic resources and insurance, but we control for these in our models. It also depends on the institutional structure that the caregiver can access easily, such as proximity to medical facilities. Neighborhood context potentially can affect some or all of the aforementioned components leading to a diagnosis. Unfortunately, we are unable to discern these mechanisms, though we do attempt to measure neighborhood institutional resources and medical facilities. Thus, we emphasize that our estimated statistical associations represent a “net impact” of the given neighborhood indicator on the odds of a diagnosis, not necessarily on the odds that the child has a neurodevelopmental disorder. The implication is that our findings here need to be interpreted with care: a statistical association should not be viewed as unambiguously good or bad normatively, regardless of its sign. If certain neighborhood attributes are, for example, associated with higher odds of a neurodevelopmental disorder diagnosis, this may be “bad” because it indicates that these places are less healthy for children. Yet, this finding may be “good” because it indicates that children who have a neurodevelopmental disorder are more likely to be diagnosed and treated.Denver Child Study survey collected information on a wide variety of child, caregiver, and household characteristics that we employed as controls; these are summarized in Our American FactFinder website utility. We successfully linked 92% of the residential locations listed by respondents with a rich set of neighborhood indicators obtained from four sources: (1) the U.S. Census via the Neighborhood Change Data Base (a Geolytics proprietary product); (2) the U.S. Environmental Protection Agency; (3) the Piton Foundation Neighborhood Facts Database; and (4) caregiver responses from the Denver Child Study. Details of the data sources and indicator construction are described in Once residential history information obtained on the survey was verified for accuracy, we geo-coded each address using the U.S. Bureau of the Census’s To get a sense of the sorts of places where our sampled children resided when they had their first diagnosis of a neurodevelopmental disorder, we present the mean characteristics of their neighborhoods in child-year becomes the unit of analysis. We estimate the probability of individual i living in neighborhood j of ever being diagnosed with a neurodevelopmental disorder using instrumental variables (IV) probit estimation and the ivprobit and margins commands in Stata 14.0 . IV probit allows the consistent estimation of a binary response model in the presence of endogeneity in some of the regressors. We name We merged the aforementioned information regarding sampled households, caregivers, children, and their corresponding neighborhood environments to create a pseudo-longitudinal database wherein the We use this model in order to account for the endogeneity that could be caused by households choosing to live in a neighborhood other than the one to which they were initially randomly assigned. For each potentially endogenous neighborhood characteristic Average marginal effects (AMEs) were calculated for each explanatory variable. For each variable and each individual in the sample, the marginal effect was calculated by finding the change in predicted probability if that variable increased by one, holding other individual characteristics constant, and marginal effects for all individuals were averaged across the sample. Delta method standard errors were adjusted for clustering within households. Continuous independent variables were standardized for ease of interpretation such that MEs correspond to a one standard deviation increase in the measure above the mean value.Although this is not a traditional two-stage least-squares model, the same requirements of relevance and exogeneity on instruments apply in order for the estimates to have a causal explanation. As we have argued previously , we belIn the first stage regressions obtained from estimating the model using a two-step procedure on the full sample, F-statistics ranged from 6.59 to 18.59, with five falling below the suggested rule of thumb threshold of 10 proposed by Staiger and Stock . HoweverGiven our binary IV probit models, classical residual analysis was not well suited for residual plots . InsteadThe results for average marginal effects (AMEs) from our IV probit estimation predicting initial diagnosis of a neurodevelopmental disorder during childhood are presented in Social vulnerability was associated with a 40.6 percentage point increase in the probability of being diagnosed;Occupational prestige scale was associated with an 18.3 percentage point increase in the probability of being diagnosed;Resident instability was associated with a 12 percentage-point decrease in the probability of being diagnosed;The proportion of housing stock built before 1940 was associated with an 18.5 percentage-point increase in the probability of being diagnosed;The neurological hazards index was associated with a 42.7 percentage-point decrease in the probability of being diagnosed.Of more central interest to our study, a number of contemporaneous neighborhood indicators related to social vulnerability and prestige, residential instability, age of housing stock and pollution were robust, statistically significant predictors of a neurodevelopmental disorder diagnosis during childhood. In overview, for a one standard deviation-higher neighborhood:In overview, the results reported above clearly show that many aspects of neighborhood physical and social context are statistically and substantively important predictors of a neurodevelopmental disorder diagnosis during childhood. Since they are produced in a natural experiment mimicking random assignment, we will discuss them as if they were indicative of causal effects. Below, we organize the discussion around thematic categories of neighborhood social context.Neighborhood social vulnerability and occupational prestige proved strongly predictive of increased diagnosis of a neurodevelopmental disorder during childhood, consistent with the aforementioned empirical literature on neighborhood socioeconomic status and child development. Consistent with prior studies ,14, our We also found evidence that older housing in the neighborhood may provide a less sanguine environment in which to raise children. We cannot know from our study whether this association may be due to the environmental conditions inside these older houses and yards (such as the presence of lead paint) in which neighbor children may conduct much of their routine activities or whether associated urban density and design features in older Denver neighborhoods may be responsible. Nonetheless, the positive association between higher fractions of older housing and a neurodevelopmental disorder diagnosis supports conventional medical wisdom regarding the deleterious consequences of exposure to toxicants for child development (see review in Emerson ).Although we found a strong, significant negative association between the presence of higher levels of neurological hazards and diagnosis of a neurodevelopmental disorder, we believe this may be an instance where caregivers and others residing in these neighborhoods might see their children’s behaviors as normative or, unlike asthma, are less likely to associate ambient air quality with the formation of such disorders. Additionally, while young children are more likely to be tested for lead poisoning, they may not be as likely to be tested for effects of other air toxicants unless they have asthma. Diagnoses of neurodevelopmental disorders also tend to be made once children start attending elementary school where intellectual, developmental, or behavioral difficulties are more likely to be noticed and thus tested.In an earlier work , we alsoOur findings found an intriguing relationship between neighborhood instability and the probability of a neurodevelopmental disorder diagnosis during childhood. Children residing in neighborhoods experiencing a considerable churn of residents were less likely to be diagnosed with a neurodevelopmental disorder. While the literature has discussed links between the residential stability of the child and these disorders, there has been little discussion about the role that resident churn might play in delaying such diagnoses. Perhaps this reflects a decrease in connections to neighborhood information networks, weakened norms and social ties to neighbors—connections which might facilitate knowledge about and help-seeking for such disorders, as well as provide social support to affected children and their families .Community health providers, practitioners and policymakers have a professional obligation to encourage the development and maintenance of economically and ethnically diverse neighborhoods and expand opportunities for disadvantaged citizens. Our research provides further impetus for progress toward these goals because it demonstrates that the most fundamental, indispensable cognitive benefits would redound to low-income Latino and African American children. We make this strong assertion because we have an unusual opportunity to measure child context-developmental associations that are plausibly produced by causal processes. An innovative public housing program instituted by the Denver Housing Authority provides a unique opportunity to explore this issue because the DHA mimics a random assignment to a wide range of neighborhoods for families with children who apply for DHA housing as evidenced by the variations from the average of our indicators, thereby enabling us to examine potential effects in disadvantaged and affluent neighborhoods. Moreover, families typically reside in DHA housing for nontrivial periods, thus producing sustained exposure to context.We employed IV probit estimation and calculated average marginal effects to determine the predictors of a low-income minority child’s initial diagnosis of a neurodevelopmental disorder. Several aspects of neighborhood social  and physical  contexts proved statistically and substantively important predictors of an initial diagnosis. We caution, however, that it is sometimes unclear whether these associations were manifested by causal links though the probability of a child exhibiting adverse neurodevelopmental symptoms, or through the probability of having presented symptoms that were medically diagnosed.Although we contend that our approach offers important advances in providing convincing evidence of causal connections between neighborhood social context and child neurodevelopment, we acknowledge that our study has weaknesses. The first shortcoming is that our measure of child health is retrospectively reported by caregivers. We recognize that this can yield random errors associated with the timing of initial diagnosis, though we have no reason to suspect rampant inaccuracies in reporting whether the diagnosis occurred. To the extent that these random recall errors affected our data, they would push the neighborhood effect findings toward null. Second, although we have an unusually comprehensive set of neighborhood indicators, we recognize their limitations in describing the physical environs in and around the home in particular. Third, we have not attempted to probe in this paper potential pathways through which neighborhood environment may affect children’s development, especially as they might unfold through exposure to violence and a variety of other behaviors . Fourth,Despite these caveats, our results clearly suggest that healthcare providers, educators, community practitioners, and policymakers should be cognizant of both the social and physical aspects of neighborhoods as important developmental contexts affecting children’s health. Given our study design, we are confident in claiming that neurodevelopmental disorders are influenced by more than personal, family, dwelling or physical environmental characteristics of low-income, minority children. The daunting policy challenge is delineating how to best encourage the development and preservation of safe, diverse neighborhood environments that can be more developmentally nurturing for all children ,67.


Ischaemic renal disease as result of atherosclerotic renovascular disease activates a complex biological response that ultimately leads to fibrosis and chronic kidney disease. Large randomised control trials have shown that renal revascularisation in patients with atherosclerotic renal artery disease does not confer any additional benefit to medical therapy alone. This is likely related to the activation of complex pathways of oxidative stress, inflammatory cytokines and fibrosis due to atherosclerotic disease and hypoxic injury due to reduced renal blood flow. New evidence from pre-clinical trials now indicates a role for specific targeted therapeutic interventions to counteract this complex pathogenesis. This evidence now suggests that the focus for those with atherosclerotic renovascular disease should be a combination of revascularisation and renoprotective therapies that target the renal tissue response to ischaemia, reduce the inflammatory infiltrate and prevent or reduce the fibrosis. Reactive oxygen species are produced as part of normal cellular metabolism and as a result of environmental factors such as pollutants. They are highly reactive and can damage cell structures. Such oxidative damage results from an excess of oxidant radicals and because of insufficient degradation of these by antioxidant systems that serve as defence mechanisms . OxidatiThe kidneys are actually extremely metabolically active organs as they receive 25% of the total cardiac output and consume 7% of daily energy expenditure to support their various functions. They are in turn highly susceptible to oxidative damage. The mitochondrial respiratory chain and nicotinamide adenine dinucleotide phosphate(NADPH) oxidases are the main source of free radicals in the kidney, whereas its defences include antioxidant enzymes such as superoxide dismutase and catalase .The related pathophysiological processes of inflammation, oxidative stress and fibrosis leading to tissue injury;Biomarker evidence for the importance of oxidative injury;The application of imaging techniques to determine intra-renal ischaemia;Emerging therapeutic strategies to counteract this complex pathogenesis.Ischaemic kidney disease, also referred to as ischaemic nephropathy or atherosclerotic renovascular disease (ARVD), is a form of CKD in which oxidative stress plays a pre-eminent role in pathogenesis. In this review, we will consider the following aspects of ischaemic renal disease, with evidence deriving from both pre-clinical studies and from patients with ARVD:A literature search was carried out that included the published literature from January 2010 to January 2020 that focused on the pathophysiology of atherosclerotic renovasular disease. Information was retrieved from PubMed through the National Library of Medicine using keywords such as “atherosclerotic renovascular disease”, “oxidative stress and ischaemic nephropathy” and “inflammation and ischaemic nephropathy”. The search yielded 612 papers, including randomized control trials, original articles, review articles, clinical trials and original research. These articles were evaluated based on how relevant the article was and if the article addressed a research question related to the pathophysiology and treatment of ischaemic nephropathy. Articles were excluded if they were deemed irrelevant to the purposes of this review. Sixty-six of these were considered relevant to the topic. Other manuscripts were located through reference lists of relevant articles. Some articles were included that were published before 2010 as they had established important concepts and knowledge that were relevant to the topic.Atherosclerotic renal artery disease is a common condition that increases with age and is known to affect 7% of those aged >65 years in the community . When asIn previous decades, there was a huge interest in revascularisation as a potential cure for both the associated renal impairment and renovascular hypertension with a large increase in the number of revascularisation procedures . HoweverPrevious animal studies had suggested that the main insult resulting from renal artery stenosis (RAS) was a haemodynamic one as a result of progressive occlusion of the renal vasculature leading to hypoperfusion and ultimately ischaemic kidney disease. Studies in porcine models have shown that renal perfusion does not decrease until there is a reduction of >42% in the lumen diameter with a dramatic drop once the RAS >70% of the diameter. Concordantly, plasma renin activity starts to increase once there is a reduction of >58% of the diameter. Interestingly, a threshold RAS diameter for an increase in mean arterial pressure (MAP) was not identifiable , which sIn recent years, there has been a shift in the understanding of the disease and recognition that in many cases there is a large inflammatory/pro-fibrotic component that leads to injury that cannot be addressed by revascularisation alone. Pathology specimens of patients with renovascular disease have shown inflammatory infiltrates of macrophages that contribute to fibrosis . As wille insult . This suThe initial reduction in renal blood flow associated with renal artery stenosis (RAS) leads to activation of the renin-angiotension-aldosterone system (RAAS), a physiological response that leads to increase in MAP in order to restore perfusion pressure in the kidney beyond the stenosis. Some studies have implicated that this initial increase in renin and angiotension II is part of a self-perpetuating mechanism that maintains systemic vasoconstriction  since rifibrosis . The actMuch of our recent understanding has been derived from pig models. Following experimental induction of RAS, levels of prostaglandin G2 e stress . As stene stress . This pegenation . MCP-1 igenation . TGF-α ed kidney . Hence, Chronic hypoxia ultimately leads to apoptosis of epithelial cells, which in turn further activates inflammatory and fibrotic pathways that contribute to progression to ESKD . Microva(1)Isoprostanes, which are prostaglandin-like substances produced independently of the cyclooxygenase (COX) enzymes but mainly via oxygen radical-induced peroxidation of arachidonic acid . Studies(2)Thiobarbituric acid reactive substances (TBARS) have been widely used as measures of lipid peroxidation in biological fluids. They are considered a reliable indicator of oxidative stress . Animal (3)Neutrophil gelatinase-associated lipocalin (NGAL) is an acute-phase protein expressed by activated neutrophils and tubular epithelial cells when exposed to both inflammatory and ischaemic conditions . It is c(4)Insulin-like growth factor binding protein 7 (IGFBP-7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) are both biomarkers of cell cycle arrest, which are often elevated in ischaemic conditions. When exposed to oxidative stress, renal tubular cells produce and release IGFBP 7 and TIMP-2, which stimulate the expression of p53, p21 and p27, all of which affect the cell cycle promotion resulting in transient arrest of the cell cycle . SustainOxidative stress develops due to an imbalance of exposure to free radicals mainly derived from oxygen and of antioxidant defences such as gluthathione and antioxidant enzymes such as superoxide dismutase. Several markers of oxidative damage exist , includiBoth of these factors have been validated as urinary biomarkers for acute kidney injury in intensive care settings .Renal vein levels of NGAL, IGFBP7 and TIMP-2 are elevated in those with stenotic vascular lesions and decrease immediately post revascularisation; however, they are seen to return to baseline 3 months after revascularisation. As stated previously, the processes of inflammation and injury in the RAS kidney persist long after renal revascularization .2 between the blood vessels of the medulla and cortex. Oxyhemoglobin is diamagnetic and deoxyhemoglobin is paramagnetic, which leads to local dephasing of protons and an increase in “relaxivity” during MRI that is known as R2*. The amount of deoxyhemoglobin functions as a contrast agent. The cortex is identifiable due to it having lower R2* levels, with increasing levels seen in deeper medullary regions [Blood-oxygen-level-dependent (BOLD) magnetic resonance imaging is a functional MRI technique that relies on regional differences in blood flow to reflect tissue oxygenation. Due to the countercurrent arrangement of intra-renal vessels and renal tubules to facilitate water reabsorption and the formation of concentrated urine, there exists a gradient of PO regions . MRI stu regions .Renal hypoxia can be an important contributor in many cases of all-cause progressive CKD, as hypoxia acts as a stimulus for the inflammatory pathway and eventually to fibrosis . PreviouBOLD MRI has also been used to highlight the decreased cortical oxygenation in those with ARVD, and this has potential to a be a valuable tool to highlight kidneys under ischaemic stress. A study that included 30 patients with atheromatous RAS, 17 of whom were considered severe as defined by ultrasound velocities more than 384 cm/sec, illustrated that cortical R2* levels were elevated in those with severe ARAS in comparison to those with either essential hypertension or even moderate ARAS. This indicates that kidneys with more severe RAS lesions are unable to adapt to the reduced renal blood flow as shown by overt cortical hypoxia measured by BOLD-MRI. In contrast, moderate RAS was associated with preserved cortical and medullary oxygenation, indicating an adaptation to reduced renal blood flow that may explain how renal function can remain stable throughout treatment with anti-hypertensive therapy such as renin-aldosterone-angiotensin inhibition in patients with ARVD .BOLD MRI may also help in the management of those with atheromatous RAS by identifying kidneys at risk of further injury. Demonstration of cortical hypoxia may be used to discriminate between acute and chronic lesions and thus identify those most likely to benefit from revascularisation, this being more applicable to the acute situation. One study using 3.0 Tesla MRI examined patients with RAS who would have met the entry criteria for the CORAL trial and who were receiving renin-angiotensin-aldosterone inhibitors. R2 levels in those with a stenotic lesion sufficient to cause an elevated level of renin were similar to those with essential hypertension, indicating a protective effect of RAAS inhibition in maintaining oxygenation. However, the medullary R2* response to furosemide administration was reduced in those with a stenotic lesion compared to the contralateral kidney, which increased its metabolic activity as compensation for the stenotic kidney . Such coAtheromatous RAS leads to reduced oxygenation and reduced GFR. Studies have shown a correlation between changes in oxygenation as seen on BOLD imaging and the increased inflammatory biomarkers that have been described previously. Reduced blood flow in RAS kidneys with resulting tissue hypoxia is associated with higher levels of NGAL and MCP-1. In the study of 30 ARVD patients by Hermann et al. that included , levels of both NGAL and MCP-1 at baseline correlated directly with all levels of hypoxia in the stenotic kidney. These levels did not return to normal with either intensive medical therapy or revascularisation. Despite restoration of blood flow, there was a strong relationship between the biomarkers and BOLD assessed residual hypoxia at 3 months post revascularisation . This suLarge randomised control trials such as ASTRAL  and CORAVEGF is a pro-angiogenic factor that promotes cell division, survival and mobilisation of endothelial progenitor cells and also vascular proliferation . It alsoIn animal models of non-renovascular CKD, VEGF treatment has been shown to preserve the microvascular architecture, and it stimulates endothelial progenitor cells, which in turn leads to more stable renal function and slowing of disease progression ,44. SpecMesenchymal stem cells (MSC) are multipotent adult cells that have the ability to differentiate into several cell types. They have been shown to be effective in several animal models of renal disease, with roles in repair and reducing renal injury demonstrated in CKD . In swinc kidney . These sA phase 1 trial has investigated the potential of autologous adipose-derived MSCs infused through the renal artery in 21 patients with ischaemic nephropathy. Three different dose levels were used (each in 7 patients) and were compared to 18 medically managed patients. The MSC treatment resulted in a significant drop in hypoxia and inflammatory cytokines, with a fall in blood pressure and an improvement in GFR. The benefit was greatest in those receiving the highest MSC dose .There is currently ongoing trial determining whether an infusion of participants’ own MSCs, harvested from a fat pad biopsy and given prior to angioplasty, enhances renal blood flow and renal function post revascularization .As discussed earlier, inflammation plays a key role in the pathophysiology of ischaemic nephropathy with elevation of biomarkers such as NGAL, TNF-renchyma .Previous studies in other causes of chronic renal disease such as glomerulonephritis have shown benefit from using immunodepleting therapy, such as mycophenolate mofetil to reduce the inflammatory infiltrate of macrophages and lymphocytes and in turn reduce sclerosis and proteinuria. Interestingly, the benefits of such therapy has also been shown in non-immune models of disease, with a reduction of progression of renal function and histological changes . Such anChronic inflammation ultimately leads to renal fibrosis, which is a common final pathway in progression of CKD to ESKD. In ischaemic nephropathy, the activation of the RAAS and increase in oxidative stress and inflammation all lead to the development of renal fibrosis. Given its key role, therapeutic interventions to prevent or delay the progression of fibrosis have the potential to have significant impact .TGF-rategies . Fresolinditions .2 in the treated patients compared to a decrease of 2.2 mL +/−4.8 mL/min/1.73 m2 (p = 0.026) in placebo treated patients [Pirfernidone is an orally active anti-fibrotic agent that has been used in multiple conditions including pulmonary fibrosis. In animal- and cell-based models, it has been shown to be an effective anti-fibrotic treatment due to its modulating effect on cytokines and reducing TGF-β . Its effβ , post suβ  and diabβ . In thespatients .Although pirfenidone has not been assessed in clinical trials of ischaemic nephropathy, in an animal model of renal ischaemia prophylactic pirfenidone conferred protection against the resulting AKI. It was demonstrated that pirfenidone had an antioxidant effect that was possibly mediated by improvement in nitrate generation after the ischaemic insult. There was also a reduction in the urinary albumuria: creatinine ratio (ACR) in those treated with pirfenidone . The posIschaemic nephropathy is far more complex than simply being due to a haemodynamic issue; multiple pathophysiological pathways, with prominence of inflammation and oxidative stress, interact to ultimately lead to fibrosis, progressive renal impairment and, if left unchecked, to ESKD. To date, therapeutic interventions have focused on reducing risk factors with RAAS inhibition, lipid lowering agents and hypoglycaemic agents in those with diabetes long with renal revascularisation. Our current approach thus overlooks the complex interactions at play distal to the stenotic lesion in the renal parenchyma in which oxidative stress and chronic inflammation often persist.The pre-clinical and human evidence now suggest that where a clinical indication for revascularization is present, the focus should be on renoprotective therapies that combine this with novel therapeutic interventions that directly target the renal tissue response to ischaemia, reduce the inflammatory infiltrate and prevent or reduce the fibrosis.


Israel, the UK, the USA, and some other wealthier countries lead in the implementation of COVID-19 vaccine mass vaccination programmes. Evidence from these countries indicates that their ethnic minorities could be as disproportionately disadvantaged in COVID-19 vaccines roll-out as they were affected by COVID-19-related serious illnesses. Their disadvantage is linked to their lower social status and fewer social goods compared with dominant population groups.Albeit limited by methodology, early studies attribute lower uptake of COVID-19 amongst ethnic minorities to the wider determinants of vaccine uptake, hesitancy or lack of vaccine confidence, including lower levels of trust and greater concerns about vaccine safety. Early sentinel studies are needed in all early adopter countries.One emerging theme among those of reproductive age in minority communities concerns a worry regarding COVID-19 vaccine’s potential adverse effect on fertility. Respected professional groups reassure this is not a credible rationale. Drug and vaccine regulators use understandable, cautious and conditional language in emergency licencing of new gene-based vaccines. Technical assessments on whether there is any potential genotoxicity or reproductive toxicity should be more emphatic.From a public health perspective, sentinel studies should identify such community concerns and act early to produce convincing explanations and evidence. Local public health workforces need to be diverse, multiskilled, and able to engage well with minorities and vulnerable groups. The local Directors of Public Health in the UK are based in each local government area and have a remit and opportunity to stimulate speedy action to increase vaccine uptake.During the rapid Pandemic Pace of the vaccines roll-out, extra efforts to minimise uptake variations are likely to achieve improvements in the next year or two. We expect variations will not disappear however, given that underlying inequalities persist in less inclusive social systems. Globally the race is on in rolling out the vaccine against COVID 19. The most successful countries in population vaccination against COVID 19 are Israel, the United Kingdom (UK), the United Arab Emirates (UAE), the United States of America (US) and Chile. The emerging evidence from three of these countries  indicates that the uptake of the COVID 19 vaccine is lower amongst these countries’ ethnic minorities.However, the concept of ethnic minorities is often used as though it refers to a constant state of being and homogenous group. In the UK, ethnic minorities refer to all ethnic groups except the White British group, mainly blacks and Arabs and Asians . Israel’Harris 2021) defines “ethnic minority” as “a group of people who differ in race or colour or national, religious, or cultural origin from the dominant group, often the majority population of the country in which they live [021 definIt is indisputable that the ethnic minorities in the western context were disproportionately affected by COVID-19-related serious illnesses; it also seems that their engagement with the vaccination programmes is low.However, the representation of ethnic minorities in the literature and media could erroneously lead to the belief that there is something innate about them that increases their vulnerability and hesitation to engage with covid-19 vaccine programmes. The ethnic minority are socio-demographic and culturally too diverse to share innate qualities that make them vulnerable to COVID-19 or vaccine reluctant or hesitant. The main similarities amongst the ethnic minorities across countries is the social status ascribed to them by the dominant group in each country. Generally, such social status reduces their freedom to fully participate in social goods such as housing, employment, social services, and healthcare services. This creates vulnerability to COVID-19-related serious illnesses, distrust, and lower access and engagement with vaccination programmes.This commentary is inspired by the study report of respondents to an internet survey reported by Green, Abdullah, Vered and Nitzan in the Israel Journal of Health Policy Research . Like moEarly warning signals that vaccine uptake is lower amongst the minority ethnic groupsDeterminants of lower uptake by ethnic minoritiesNeed for systematic sentinel alert systems covering variations in uptake of COVID 19 vaccineHow minorities feature in COVID-19 vaccine priority frameworksReproductive health and Infertility as a specific minorities concernWhy governments, public health systems, scientists, academics and regulators need to accept a greater share of responsibility around reassurance as more gene-based vaccines become availableHow the public health workforce can respond effectively to narrow these gaps over timeThis commentary presents our observations of the UK, US and Israel’s experiences in rolling out COVID-19 vaccination, exploring seven underlying themes;Countries with strong public health systems have achieved some early successes in rolling out and vaccinating their populations. Some of the early examples of success in rolling out vaccine are Israel, the United Kingdom (UK) and lately, the United States of America (US).However, the emerging evidence from these countries suggests that ethnic minorities and other vulnerable social groups may be getting further left behind for various reasons, including vaccine hesitancy.pre-existing frameworks for making decisions that involve public health and other experts in vaccine advice;the Israel National Immunization Technical Advisory Group (NITAG);strong systems of electronic population health registers and patient records,high levels of enrolment in healthplan organisations.Israel has led worldwide in the fast rollout. Recent analyses clarify factors that influenced Israel’s fast rollout , 5. The Glied pointed to the Israeli vaccine programme’s success arising from the coherent and well-resourced national vaccine strategy, built upon the country’s effective, resilient healthcare system, that is well versed in responding to other emergencies .However, the evidence shows that the vaccine’s uptake was lower amongst the minority groups in Israel . The higSimilar findings have emerged in the earliest major UK studies. One of the largest early UK retrospective cohort studies; covered an overall 961,580 vaccinated people within 23.4 million GP registered study population , the RoyHealth service providers’ concerns were also being raised about lower uptake in NHS healthcare workers from different BAME backgrounds . Since tLower trust and confidence in vaccine efficacy and safetyLower perception of riskInconvenience and access barriers, including costsContext and socio-demographic variation, including levels of education.The UK Scientific Advisory Group for Emergencies (SAGE) ethnicity sub-group review in December 2020 looked at factors influencing COVID-19 vaccine uptake among minority ethnic groups and other minority issues , 15. TheThe study by Green and colleagues challenges the theory that lower perception of infection risk is the main factor in COVID-19 lower uptake . In theiTimely information about the progress of rollout can guide policymakers and program directors at all levels. And, of course, sentinel information should be tailored to local demographics.In Israel, an immediate challenge was to address the hesitancy among the educated women in the Arab population . In the That vaccines may contain the live (coronavirus) virusThat there will be out of pocket expenses, that vaccine is not free and might require health coverage documentation, or that personal data collected could be transferred to other agencies,That younger age groups are more hesitant than older and more likely to wait and see Short-term fears of losing time from work to longer-term concerns about Infertility.That health professionals are held in the highest regard and with reasonably high regard for public health agencies. Also, that family, friends, and religious leaders are relatively higher key influencers in a sizeable proportion and need to be positively engaged.In the US, the earliest report of variation in uptake of COVID 19 amongst the minorities came from CDC, but had had a large percentage of missing data on ethnicity or race . The KaiEarly insights should allow policymakers and program directors to address such minority group concerns about composition of vaccines, extra personal costs or loss of income from more severe side effects. Vaccination programmes are mainstream social programmes that everybody is expected to participate in. Arguably, in societies where minorities are relegated towards society’s margins, they may be more reluctant to participate in those mainstream programmes. Early reports, cited above, could not attribute underlying causation. Studies on perception and opinion offer partial insight but do not report on structural facilitators or barriers to service use. There was little initial reportage on wider determinants of vaccine uptake in relation to social position, power, and inclusiveness.This pandemic has demonstrated both the importance of developing a prioritised set of vaccine recommendations and recognising that the recommendations and their priority may need to change over time. In the UK, the Joint Committee for Vaccination and Immunisation (JCVI) initially prioritised vaccine recommendations based on clinical risk as determined by age, clinical conditions, and health and social care worker status . In theiAlthough the initial JCVI recommendations were based on the above evidence, the pandemic has demonstrated that other factors should also be considered. These include an ‘intersectional human rights’ approach balancing risk and benefits across society . TherefoGreen and colleagues’ study shows that educated Arab women respondents raised some concerns about the potential effects of the COVID-19 vaccine on fertility. This was important for them since they were, on average, about ten years younger than Jewish respondents .The UK based Association of Reproductive and Clinical Scientists and the British Fertility Society, the Human Fertilisation and Embryo and Authority, and the Royal College of Obstetrics and Gynaecology, have issued statements to counteract the misinformation that COVID-19 vaccines could potentially impact male or female fertility –28.The British Islamic Medical Association (BIMA) also provided reassuring information for patients in regard to infertility concerns, and in BIMA’s case, also on other myths such as about COVID-19 vaccine containing non-Halal or alcohol-based constituents .There has been measured and cautionary reassurance around vaccine safety, as there is ongoing research to establish with certainty the safety of these vaccines. However, the modern scientific movement towards Gene-Based Vaccine technology deserves further consideration.Vaccine hesitancy has proven to be a global concern. Addressing it will require each country sponsoring a vaccination program to address this issue for its own population. Since some lessons about addressing vaccine hesitancy are likely to be generally applicable, ideally countries would work together to understand and spread the best practice . CountriThere is a need to understand better if some rapid COVID-19 vaccine policy and technical reviews have built or eroded public trust or vaccine confidence. It has been contended that India’s government may have been overly hasty with lack of transparency in India’s vaccine (Covaxin) licensing arrangements .Normally vaccine licensing relies on the publication of satisfactory Phase 3 human studies. It appears that in some countries, such as India and Russia, rollout followed smaller Phase 2 studies –36. TherThe continuing metanalysis of studies into COVID-19 during pregnancy shows that women being of non-white ethnic origin might also be a risk factor for severe covid-19 infection . This isThere are large numbers of Gene-Based-Vaccine candidates under development for COVID-19 . These aAny ensuing controversy or disagreement among medical, public health and international scientific communities is a likely media trigger that can help spread uncertainty worldwide.All countries must have modern public health risk communication strategies. In the UK, public health risk communication advice was first issued in 1997. It was generated by communication mistakes and harsh lessons from public health crises of confidence and controversies, such as with the variant Creutzfeldt-Jacob (vCJD) outbreak from Bovine Spongiform Encephalopathy (BSE) or ‘mad-cow disease’ infecting beef, Salmonella in UK egg supplies, and the Mumps, Measles and Rubella (MMR) vaccine controversy . BennettSeveral agencies and expert groups are engaged in with COVID-19 vaccine rollout within the UK, such as the JCVI and MRHA . All perform meaningful and valued roles but may give scope for inconsistency in the message or in emphasis. The UK COVID-19 Vaccine Task Force has led forcefully on vaccine procurement, supporting vaccine industry development, and supporting international aid and supplies. However, their 2020 end of year report made claims for a comprehensive communication campaign . This isA wider communications challenge is the understandably cautious technical and legal language used in conditional approvals or emergency-use licensing –47. COVIMedicines and vaccines regulators should inspire wider trust and take credit for rapid comprehensive reviews of vaccine trial studies. However, overly enthusiastic rhetoric of leaping forward and a revolution in vaccine technology  might reRigorous approaches are needed to set up and run successful vaccination programmes . Many diA Kaiser Family Foundation recently reported many local public health and state’s innovative and responsive measures scattered across the USA. All responses should be evaluated rigorously to learn for future vaccine rollout-out and wider public health practice to reduce health inequalities . Their vThe 1997 UK public health risk communication guidance advised to engage and build trust carefully, not to overlook basic stakeholder concerns, and to investigate and communicate in a two-way process throughout the timescales . Razai aFirstly, the pivotal role of DsPH has been better recognised recently, rather than being marginalised by central government earlier in the pandemic. Secondly, DsPH are geographically closer to their populations . Thirdly there is some diversity of gender and ethnicity in that group of 23 DsPH. Finally, the UK multidisciplinary specialist public health workforce allows DsPH to represent differing skillsets. There may need to be a greater focus on cultural competency skills in the whole public health workforce in our future curricula and training programmes. Useful tools and materials have been collated for healthcare professionals from Public Health England  and the The race for vaccines goes on with the early pacesetters showing urgent minority group issues to addressed. Ultimately this is also a race between humanity versus the virus, as it spreads and mutates. For public health professionals, our race is between advancing our societies’ organised efforts to promote widest population protection and equity to achieve universal coverage while battling the brakes of community hesitancy and systems disruption.Pandemic pace implies accelerated emergency development of biotechnologies, with an understanding that ‘every day counts’ . PerceptThe rollout of vaccines against SARS-CoV-2 in several countries have had differential uptake between the majority and minority populations. Although there has been some evidence of vaccine hesitancy and resistance in all populations within each country, the phenomenon appears to be greater among the minority populations. This is particularly unfortunate since these same minority populations have had higher attack rates of disease due to SARS-CoV-2 and should benefit more from the vaccines. It looks possible for localised public health systems to identify and diminish vaccine hesitancy through local disease and risk-perception surveillance and by further building trust and even closer engagement with ethnic and other minorities and by adapting vaccination services for greater fit with each minority community.All countries should develop strong vaccine data systems, to analyse and report uptake data suitable to their minorities composition. Ethnicity terminologies in our countries can be contentious and global thinking about minorities classification need to be updated .Public health research should focus on the underlying determinants of disadvantage and exclusion as well as vaccine perceptions and vaccine access factors. They should avoid furthering stigma, blame and further discrimination for excluded groups and report objectively on structural determinants and any discriminatory or racist policies or exclusion.Vaccine programs should promote speedy sentinel alerting studies, such as with the Israel example  and the All country-level vaccine prioritising frameworks should recognise higher infection risk in minorities and specify strategic goals for high uptake and equity. Where vaccine certification or passports are introduced , they shPublic health professions and scientists should give coordinated attention to any concerns about perceptions of potential long-term effects, such as about reproductive toxicity and Infertility. A danger is with newer gene-based vaccines, including genetically modified technologies for other target infections, that wider vaccine distrust could grow, giving greater energy to modern infodemics or to sources of active health misinformation and anti-vaccination proponents.Policymakers should work closely with regulatory agencies to evaluate both efficacy and safety and pursue rapid, open scientific publication of evidence reviews. The pandemic’s emergency vaccine authorisations have understandable conditionality and cautious language. Uncertainty or precautionary messages can be exploited by those with anti-vaccination motives and encourage greater ‘hesitancy’ in some social groups. Policymakers should update frameworks for assessing vaccine efficacy and effectiveness further than recently proposed , to embrPublic health professional systems and institutions will need to be reviewed with regard to community engagement. The public health workforces will probably need to be strengthened in capacity and capability to identify and respond better to communicable disease inequalities and variations in vaccine uptake at the locality level and integrate enhanced supportive expertise from academic, clinical and other professional experts. We must work closely with local GP and other primary care colleagues who are trusted in their communities and should be supported in their community-based commitments and innovations .Public health policy measures from the seven themes above should include:It is not too late for policymakers to ensure that health inequalities are not further exacerbated and to learn lessons from early mass vaccination programmes . Already


We report the case of a patient with recurrent episodes of disturbed memory suggestive of transient epileptic amnesia, and a focal hippocampal lesion typically associated with transient global amnesia. We argue how careful consideration of clinical, electrophysiological and imaging findings can resolve this apparent contradiction and lead to a diagnosis of early symptomatic post-stroke seizures that links brain structure to function in a new, clinically relevant way.A 70-year-old patient was identified in clinical practice in our tertiary care centre and was evaluated clinically as well as by repeated electroencephalography and magnetic resonance imaging. The presenting complaint were recurrent episodes of short-term memory disturbance which manifested as isolated anterograde amnesia on neurocognitive evaluation. EEG and MRI revealed predominantly right frontotemporal spikes and a punctate diffusion-restricted lesion in the left hippocampus, respectively. Both symptoms and EEG changes subsided under anticonvulsant treatment with levetiracetam.Our report contributes to the current discussion of clinical challenges in the differential diagnosis of transient memory disturbance. It suggests that focal diffusion-restricted hippocampal lesions, as seen in TGA, might be ischemic and thus highlights the importance of considering post-stroke seizures as a possible cause of transient memory disturbance. Differential diagnoses for atraumatic temporary memory loss include cerebral ischemia, transient epileptic amnesia (TEA), and transient global amnesia (TGA). Diagnostic criteria for TEA are recurrent short episodes of disturbed memory; sparing of other cognitive domains; and clinical or electroencephalographic (EEG) evidence of seizure activity or response to anticonvulsant medication . Memory 1-hypointense and rather hyperintense in FLAIR images  revealed a persistent anterograde amnesia with no further cognitive impairments (score 26/30). Routine blood tests and computed tomography of the head were unremarkable. Initial electroencephalography after spontaneous resolution of symptoms showed intermittent right frontotemporal spikes followed by slow waves. They were preceded by intermittent beta waves and low-amplitude spikes in the left temporal region Fig. A; diffusDespite their definition as distinct phenotypes of transient memory disturbance, differentiation between TGA and TEA can be challenging. When clinical features are inconclusive, diffusion imaging and EEG may aid diagnosis. Their usefulness is limited, however, by the facts that the appearance of characteristic lesions in the hippocampus in TGA is often delayed  and thatConflicting positive findings, on the other hand, also present challenges. Arguing that the lesion in our patient was too circumscribed to be a postictal phenomenon, and ignoring the possibility of a coincidental finding, it follows that it played a causal role for his symptoms. While TEA is usually idiopathic, a small number of symptomatic cases caused by focal lesions in the temporal lobe have been reported previously . Diffusi1-intensity are unusual for TGA. Considering the high frequency of recurrent amnesic episodes and consistent EEG changes thus led us to the diagnosis of early post-stroke seizures.In the presented case, imaging was consistent with both a recent ischemic infarct and a TGA lesion, although the posterior location in the hippocampus and low TWe suggest that this differential be considered in cases of transient amnesia with a suspicious lesion in the hippocampus, especially if symptoms recur or are associated with epileptiform discharges on EEG, as it might inform secondary prevention and influence the medical management of the patient.