The temporal investigation of high‐risk areas of cancer incidence and mortality can provide practical implications in cancer control. We aimed to investigate the changes in spatial clusters of incidence and mortality from 1999 through 2013 by major cancer types in South Korea.We applied flexible scan statistics to identify spatial clusters of cancer incidence and mortality by three 5‐year periods and seven major cancer types using the counts of new cases and deaths and population in 244 districts during 1999–2013. Then, we compared the changes across three periods in the locations of primary clusters of incidence and mortality by cancer types. To explore the determinants that possibly affect cancer cluster areas, we compared geographic characteristics between clustered and non‐clustered areas.While incidence clusters for lung, stomach, and liver cancer remained in the same areas over 15 years, mortality clusters were relocated to the areas similar to those of incidence clusters. In contrast, colorectal, breast, cervical, and prostate cancer displayed consistently different locations of clusters over time, indicating the disappearance of existing clusters and the appearance of new clusters. Cluster areas tended to show higher portions of older population, unemployment, smoking, and cancer screening compared to non‐cluster areas particularly for mortality.Our findings of diverse patterns of changes in cancer incidence and mortality clusters over 15 years can indicate the degree of effectiveness in cancer prevention and treatment depending on the area and suggest the need for area‐specific applications of different cancer control programs. While cancer incidence directly reflects anatomical and histological characteristics and is directly affected by various risk factors,The identification of differences and similarities in clusters of cancer incidence and mortality over time can suggest future directions in evidence‐based interventions for cancer control. The geographic gap between incidence and mortality clusters could suggest the shortcomings in different prevention stages. The areas identified as an incidence cluster may indicate the limited effectiveness of health‐promoting and/or successful implementation of early‐detection programs, whereas a mortality cluster could mean the limitation in preventing severe symptoms and avoidable disabilities related to cancer mortality. Besides, the overlap of incidence and mortality clusters could suggest the difficulty in all stages of cancer prevention activities. Furthermore, cluster distribution in incidence and mortality could be consistent or vary over time and by cancer type, which provides the insights into the prioritizing areas of future interventions and the identification of geographic risk factors.High burden of cancer and well‐established cancer registry in South Korea allow us to investigate cluster patterns of cancer incidence and mortality over an extended period. In South Korea, cancer has been a leading cause of death since 1983.22.1https://kosis.kr/eng/). We selected the seven cancer types based on high incidence or mortality in South Korea. We defined the type of cancer by the International Classification of Diseases 10th revision  (on Table . Districhttps://sgis.kostat.go.kr/). South Korea was composed of seven Metropolitan Cities and nine Provinces during 1999–2011  for 1999–2013.We obtained shapefiles of district boundaries from the Statistical Geographical Information Service . The CHS was designed as a nationwide, community‐based, and cross‐sectional survey that aims to produce comparable health statistics across districts.We used 11 geographic characteristics including demographic, socioeconomic, health‐related behavioral, and healthcare features Table . These d2.22.2.1We identified spatial clusters using the scan method which is the most common approach of spatial cluster detection.In our cluster analysis, using the counts of new cases and deaths as well as population across 244 districts, we applied flexible scan statistics along with Poisson model by three different periods and seven cancer types.We performed two sensitivity analyses to examine the robustness of our findings. First, we decreased the window size to 10% and 5% of the total number of districts and compared the cluster locations to those from our primary analysis using 15%. Additionally, we carried out the same cluster analysis by two sexes separately.2.2.2https://www.r‐project.org/).To examine geographic characteristics that possibly distinguish clustered districts from non‐clustered districts, we compared 11 health‐related characteristics by seven cancer types during the last period for 2009–2013. We compared each characteristic between cluster versus non‐cluster districts by incidence and mortality. Because some clusters are composed of small numbers of districts less than five, we included all statistically significant clusters including primary and secondary clusters in order to retain sufficient numbers of districts for comparison. All statistical analyses were implemented in R version 4.1.3 with the “rflexscan” package for cluster analysis . Preventable death is defined as causes of death that can be avoided by implementing effective public health and primary preventive interventions before the stage of disease onsets, while treatable death is characterized as avoidable deaths through timely and effective health care interventions including secondary prevention and treatment after the onset of disease.Geographic characteristics partly explain the distinctive properties in cluster areas compared to non‐cluster areas. The cluster areas of incidence in 2009–2013 were characterized by older population, higher unemployment, higher current smoking rate, and higher cancer screening rate than those of non‐cluster areas in all but breast cancer. These patterns were found even stronger in mortality. Breast cancer was an exception in that cancer screening rate in incidence clusters was higher than non‐cluster areas, while the lower rate was found in mortality clusters. These findings are consistent to previous literature. For example, lung cancer clusters were found in the areas with high smoking rate in China and low socioeconomic status in Pennsylvania, United states, while colorectal cancer clusters were detected in the areas with high screening rates in North Carolina, United states.We applied flexible scan statistics that allow us to overcome the limitations of traditional scan methods.Our study includes several limitations that promote further studies. First, we investigated the patterns of changing clusters from 1999 through 2013, but this 15‐year period may not be sufficient to observe the complete pattern of changes. The decreasing trend of nationwide cancer incidence and mortality rates beginning in the middle of 2010s, as interpreted as the achievement of nationwide cancer control programs, also suggests the need of the extended investigation. Future studies should re‐examine the changes by adding the updated cancer data for the latest periods. Second, we did not account for age structure in our cluster detection. As cancer incidence and mortality tend to be high in the areas with high proportion of order adults, cluster analyses for cancer could have used age‐standardized rate or have adjusted for age when aiming to identify new clusters or new risk factors after excluding the impact of age structure. However, our study focused on the temporal changes in the locations of spatial clusters and their potential relationships with cancer control actions which also include older adult population. Third, our investigation of geographic characteristics focused on the difference between clustered and non‐clustered areas in the period 3 rather than the change of cluster locations across three periods, because of data limitation. The addition of geographic characteristics in addition to cancer incidence and mortality data in the latest periods can allow us to investigate the relationships of changes in geographic characteristics and changes in cancer clusters. Finally, the local characteristic description of cluster versus non‐cluster areas may not confirm the causal relationship between health risk factors and cluster areas. Further studies could investigate whether cluster locations change depending on the adjustment and apply a novel approach to investigate the causal association with geographic risk factors.5Our study investigated the temporal changes in the spatial clusters of incidence and mortality over 15 years since nationwide cancer control programs began in South Korea and found various types of sequential changes depending on the cancer type. The change including persistence, relocation, removal, or introduction of clusters may suggest enhanced or limited effectiveness of cancer prevention and/or treatment interventions and provide practical guidance to future cancer control programs for such area.Cham Thi Nguyen: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); validation (lead); visualization (lead); writing – original draft (lead). Insang Song: Methodology (supporting); validation (supporting); writing – review and editing (supporting). Inkyung Jung: Methodology (supporting); writing – review and editing (supporting). Yoon‐Jung Choi: Investigation (supporting); writing – review and editing (supporting). Sun‐Young Kim: Conceptualization (lead); formal analysis (supporting); funding acquisition (lead); investigation (supporting); methodology (supporting); resources (supporting); supervision (lead); writing – review and editing (lead).This work was supported by the National Research Foundation of Korea (grant number: 2022R1A2C2009971) and the National Cancer Center of Korea .The authors have no conflicts of interest to declare.Ethics approval and informed consent not applicable.Data S1:Click here for additional data file.


International Journal of Health Policy and Management, recently published a scoping review of neurotrauma registries in LMICs by Barthelemy et al; from this the commentary reflects on the state of the art and how these LMIC registries could be taken to "the next level" as meaningful tools for improving major injury patient care.Since 1990 National Trauma Registries, — taking the form of "not for profit" small and medium enterprises — have been integral to improvementsin major injury case fatality in high-income settings. This is laudable but unsatisfactory as globally most years of life lost to injury occur in low- and middle-income countries (LMICs).  The global burden of injury falls disproportionately on young people living in low- and middle-income countries (LMICs)4 It has only been possible to demonstrate and publish this evidence with the data acquired, analysed, published and maintained by national trauma registries. Clinicians and Ministries of Health in LMICs — supported by the World Health Organization (WHO) Acute and Trauma Care Programme are keen to see this approach replicated in low resource settings: The current publication by Barthélemy et al “Neurotrauma Surveillance in National Registries of Low- and Middle-Income Countries: A Scoping Review and Comparative Analysis of Data Dictionaries”5 provides important insights into how feasible this might be given the “state of the art.” In recent years hospital case fatality from traumatic brain injury and multisystem injury has been shown to halve in high-income countries (HICs) — associated with improved access to skilled resuscitation and specialist neuroscience care within designated trauma care systems.5 Although the study had limitations particularly around searching it is impossible not to conclude from this review that currently LMIC trauma registries have limited capacity to support neurotrauma care improvement at national and international level — both in terms of their breadth and depth. Barthélemy and colleagues conducted a scoping review by searching the literature since 1991 for reports of national trauma registries in LMICs where the data dictionaries may be accessible, they also randomly but not comprehensively searched LMIC ministries of health. In total 15 LMICs were identified as having national trauma registries active at some point over the study period with 16 different registries, however only one registry had all the “minimum neurotrauma data” elements of the international registry for trauma and emergency care (IRTEC). Disease or patient registries are collections of secondary data related to patients with a specific diagnosis, condition, or procedure. Secondary data is extracted from the patient care record rather than requiring new patient contact making them efficient resources for healthcare quality improvement (QI), assurance and comparative effectiveness research. National and international registries are usually anonimised making data analysis ethical when used for governance, service improvement or research. In order to understand why trauma and neurotrauma registries are not ubiquitous in LMICs one must understand their development in HICs over the last 30 years.9 to improve survival and reduce disability in major injury victims. Investment in Trauma Registry reach and depth has been supported by ministries and healthcare commissioners; witnessing registry potential from published studies in single hospitals or geographical regions. Core neurotrauma data items are relatively sparse 8 in IRTEC and 40 from the Utstein template, recently replicated by the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury.12 However, for trauma and neurotrauma registries to “live and breathe” data collection and reporting needs to be continuous and updated. Trauma receiving hospitals need a designated staff member paid to enter data and a clinician supporting this and receiving the registry reports which should benchmark the performance of each hospital against its peers — international and national norms — in a recent data set. The trauma or neurotrauma lead for the registry needs to be responsible for feeding back the reports at hospital trauma audit meetings for learning, governance and QI to occur. A credible mortality risk adjustment model is also key so that hospitals can estimate whether their acute care survival is better or worse than expected, this should be possible with the IRTEC data fields to risk adjust using the Kampala Trauma Score.13 Without these feedback loops for QI, governance and learning the registry can wither on the vine and become historical and less relevant like any ageing research dataset. Trauma and neurotrauma registries have been very much a “bottom up” small or medium enterprise and not for profit development in HICs. They are the equivalent of small business “start-ups” which have taken off. The entrepreneurial spirit was born in groups of clinicians, hospital managers, data scientists and patients in Europe, North America, and Australasia. The motivation was the need for data — rather than dictat and dogma — as the primary driver informing QI, governance, research, and national guidelines“What are the obstacles to implementing emergency care/trauma registry-based systems in LMICs?”14 Given the history and requirement for a successful neurotrauma registry in resource rich settings one can guess that the barrier is not just a database and/or clinical record which IRTEC has addressed, but the ability to prioritise initiating and maintaining registry based QI and governance in resource limited settings when the actual provision of resuscitation, lifesaving treatment and training clinicians understandably take priority. However, to suggest that “it’s resources” is glib — probably oversimplifying a complex issue. Studies of why data in mass casualty incidents is so limited also suggest it is a cultural issue as much as limited resources.15 As with many small and medium enterprises success depends on leadership by key individuals, appetite for change, motivation to succeed — but resources and training in consistent reproducible data collation, reporting and interpretation for QI are also needed. In HICs resources for dedicated registry staff in the co-ordination centre are provided through a variety of funding arrangements from road traffic collision insurance companies, central ministry or surgical college funding or subscriptions from individual hospitals.8 Trauma registry co-ordination centres are usually situated within higher education institutions rather than as independent entities, and it is worth noting the efficiencies that emanate from an “all major injury” inclusion criterion rather than solely neurotrauma. The rigour of the approach taken by Barthélemy and colleagues suggest the GEMCARN questionshould be given priority by research funders. The Global Emergency Care research network (GEMCARN) prioritised 7 key questions for improving trauma and emergency care systems. The third highest priority was given to the question International Journal of Health Policy and Management scoping review from Barthélemy et al. This is an invited commentary after providing review on the  Not applicable. Author declares that she has no competing interests. Global Emergency Care Research Network (GEMCARN)/Lead applicant/GCRF-QR/£50,000/2019-20.


Exploration of science and technologies represents human's thirst for new knowledge and new life. Presently, we are in a stage of transferring the use of fossil fuels to renewable energy, which urgently calls for new energy materials and techniques beyond the boundary of human knowledge. On the way of scrutinizing these materials and surmounting the bottleneck of their performances, characterizing technologies are of critical importance in enabling the revealing of materials regarding their structural and chemical information, eventually establishing the correlations between microstructures and properties at the multiscale levels. Regrettably, traditional characterizations are hard to simultaneously probe electrochemistry with these chemical and physical structural evolutions, especially under operando conditions, or offer high‐resolution images of materials sensitive to electron‐beam irradiation. To this end, various advanced characterizing and diagnosing technologies recently developed, such as transmission X‐ray microscopy and cryo‐transmission electron microscopy, have demonstrated their benefits in understanding the energy storage behaviors of high‐performance energy materials . Benefited from new knowledge, the progress of high‐capacity electroactive materials is significantly accelerated. Here, we timely review the breakthroughs in emerging techniques and discuss how they guide the design of future battery materials to achieve the ultimate carbon neutrality. Advanced characterizing technologies are of critical importance in enabling the revealing of materials regarding their structural and chemical information, eventually establishing the correlations between microstructures and properties at the multiscale levels. Entering the 21st century, advances in technologies enable access to renewable energy sources such as solar, wind, and tide energy. Today, the realm of energy conversion and storage has become a hot spot for governmental funding and corporate investment. Exploring the suitable ways for renewable energy capturing and storage on large scale has been the mandate of the scientists and engineers to cope with the drastic energy demand and pressing expansion of modern industries.Energy is the foundation and driving force for the progress of human civilization through satisfying basic social needs and spurring economic growth.1 In t Currently, the applications of rechargeable batteries are ubiquitous, to name a few, mobile electronics, electric vehicles, and smart grids. Most typically, the rechargeable batteries based on lithium (Li)‐ion intercalation chemistries have achieved a great success in commercialization relying on their advantages in specific energy, rate capability, cycle life, and abuse tolerance. Furthermore, research into Li‐ion batteries (LIBs) has become rather attractive and climbed sharply in popularity, resulting in the birth of new Li‐storage materials and the more fundamental insight into electrodes and electrolyte. In this context, understanding both the changes upon the structure and chemistry of electroactive materials during energy storage is of critical importance, which urgently calls for advanced techniques for in‐depth characterizing and diagnosing of electroactive materials.Rechargeable battery technology is rooted in a series of electrochemical principles regarding storing electrical energy via the chemical reactions between the anode and cathode, and releasing the electrical energy through the reverse process when needed.3 CurrIn this perspective, we pay attention to the progress of advanced characterizations in deepening the fundamental understanding and fostering further development of high‐performance batteries. Specific focus is placed on transmission X‐ray microscopy (TXM) and cryo‐transmission electron microscopy (cryo‐TEM), both of which are increasingly accessible to the battery scientists. As of now, these two techniques have become mature enough to help us reveal key structural and chemical information of battery materials. Thus, we first discuss the specific capability of synchrotron‐based X‐ray imaging techniques in LIBs. Subsequently, the significant advances in the exploration of atomic structure and chemical constituents of the Li metal anode are highlighted. We believe that these fundamental insights into battery materials enabled by emerging characterization techniques are of great significance for boosting their electrochemical performances.2 Here, the real‐space imaging techniques, mainly the TXM technique  upon operando conditions and may lead to interesting findings that are previously hard to discover by conventional approaches. We will discuss the specific capability of synchrotron‐based real‐space imaging techniques in secondary batteries in the following section.Since the late 19th century, X‐rays have been applied for imaging at the first discovery. Attributing to the excellent penetration capability, X‐ray microscopy can directly and non‐destructively visualize the mechanochemistry changes within battery materials under operando conditions. Various setup and principles of the imaging systems bring two categories of X‐ray microscopic techniques that are real‐space and reciprocal space imaging methods.6 Heree Figure , are sel One typical example is the in operando observation of electrochemical and mechanical degradation in the LIBs. An electrode‐level investigation on the individual particles was conducted on the model material of tin oxide to reveal the origins and evolution of electrochemical and mechanical degradation  chemical composition and morphology on single‐particle throughout the whole electrode, raveling the lithiation mechanism, crack initiation and growth behavior during the following lithiation process. It is worth noting that this direct record image is highly related to the X‐ray attenuation coefficient, leading to high sensitivity to high atomic number Z but low Z. The utilization of phase‐contrast imaging technique that is determined by the variations in intensity can offset this disadvantage. The tracking of Li plating/stripping behavior in battery systems, especially upon operando conditions, has always been a challenge given the high activity and sensitivity of the Li element with a low atomic number. To this end, the phase‐contrast X‐ray imaging technique holds promise to provide an operando observation of the Li electrochemical behavior in practical battery systems. This is because the atomic number Z sensitivity of the phase‐contrast imaging method can distinguish the light Li element from other battery materials. For instance, the formation of porous structure and the corresponding progression revealed can significantly determine the subsequent Li plating and lead to the topologic inhomogeneity of Li metal anode  TXM‐XANES mappings, we revealed the core‐shell reaction mechanism in the layered oxides that experience small volume changes during the whole electrochemical cycle. For the electrode materials with large volume changes, another digging reaction mechanism was also demonstrated on the nickel sulfide anode material by the combination of the morphological and chemical evolution on the single‐particle.Further coupling with X‐ray absorption near edge structure (XANES) by using a continuous tunable synchrotron X‐ray source, the X‐ray spectroscopic imaging can offer chemical phase mapping that demonstrates the spatial resolved electronic structure of the mapping elements. This X‐ray spectroscopic imaging method has demonstrated its advantage in the field of battery research, where the morphological and chemical changes occur simultaneously. By leveraging the capacity of XANES analysis, TXM can give the chemical oxidization state mappings with high chemical and elemental sensitivity at a high resolution of tens of nanometers, which is critical for understanding the reaction mechanism in battery materials under al cycle.13 For The transition metal segregation induced electrochemical degradation in layered structure oxides was disclosed by the energy‐resolved full‐field X‐ray nanotomography which provided the distribution of all the transition metals  within the particles lithiation process in the single‐crystal spinel oxides cathode Figure .15]15[1s Figure .[16]3 Typically, solid electrolyte interphase (SEI) was earlier proposed by Peled et al. in 1979. Given the natural feature of the SEI itself being chemically reactive and sensitive to electron‐beam irradiation, its atomic structure and distribution are difficult to observe by conventional characterizing technologies, such as TEM and X‐ray diffraction. The real SEI structure, especially for organic phase, is rapidly destroyed by the thermal effect stemming from high‐energy electron beam irradiation. Therefore, in most cases, the X‐ray photoelectron spectroscopy (XPS) is a commonly used tool to study chemical components. However, probing an SEI structure from XPS alone is still challenging as it fails to reveal in‐plane heterogeneity at the submicron scale. The local chemical and structural information in SEI layer remain so far unknown, making the SEI layer very mysterious and becoming the least understood aspect of the battery realm. Currently, evidence is mounting that understanding the formation and evolution of the SEI layer is indispensable because of its unique role in regulating the electrolyte corrosion rate, the kinetic parameters of Li diffusion, and interfacial stability. Until recently, the emerging Cryo‐TEM technique was proposed to characterize the detailed atomic structure of Li metal and its SEI layer ‐based materials to be used for stable Li storage require the cooperation of using fluoroethylene carbonate (FEC) as electrolyte additive. An amorphous SEI was formed during lithiation, consisting of organic poly(VC) and inorganic LixSiOy layers. While in the subsequent delithiation process, a conformal surface layer remains, which is attributed to the stable poly(VC) components against the oxidation and therefore, contributing to the excellent stability of the Si anode in the FEC‐based electrolyte system. This work bridges the gap between microscale and atomic‐scale characterizations of battery electrodes, revealing the nanoscale and mesoscale heterogeneity of extrinsic interphases. Meanwhile, the Cryo‐TEM technique is also a powerful tool for direct imaging and characterization of cathode electrolyte interphase (CEI) layer preserved in native state at atomic scale since the critical role of CEI on cathode surface in preventing parasitic side reactions is increasingly emphasized. The related information will lay the fundamental for understanding the electrode evolution and battery‐failure mechanisms. New insights in CEI would help make the rational design of electrodes and electrolytes for emerging battery chemistry possible. For instance, a facile strategy based on a brief external electrical shorting design between anodes and cathodes and SEI evolution is proposed to achieve the conformal CEI layer on cathode surface. The established CEI help boosts the Coulombic efficiency and capacity retention of the cathode during the repeated cycling (Figure Besides, the Cryo‐TEM technique is also applicable to probe the underlying mechanism of why certain electrolyte formula allows the electroactive materials to have successful performances.25 Typg Figure . In a future trend, low‐dose imaging technology at cryogenic temperatures further retains its original state and structure from electron beam damage, and also can be imaged at the micro/nanoscale, or even at the atomic scale. In this context, the more accurate information is possibly revealed due to the iterative upgrading of characterizing technology. The fundamental insight into interfacial chemistries in battery materials is imperative for inhibiting uncontrollable dendrite growth and inactive Li formation in future research.Although Cryo‐TEM provides a possibility in observing Li metal and its surface by to a great extent eliminating thermal damage from electron beam to SEI layer, the long‐time irradiation will still lead to image floating and deformation, especially for organic phase in SEI layer.19 In 4In summary, the state‐of‐the‐art characterizations including cryo‐TEM and TXM highlighted in this perspective can probe the evolutions of physical and chemical properties at multi‐length scales from atomic to the electrode level, especially under the operando conditions. Coupling various techniques determine a powerful tool for comprehensively understanding the structural changes in battery materials. Further development of electron and/or X‐ray sources such as much brighter synchrotron radiation could shorten the time of data collection, which makes the real‐time observation and high spatial resolution possible. Other advanced spectroscopic, imaging, scattering, etc., techniques can also provide critical complementary information that will make significant contributions to develop next‐generation battery systems.The authors declare no competing financial interests.


Haemorrhagic shock after trauma is a leading cause of death worldwide, particularly in young individuals. Despite advances in trauma systems and resuscitation strategies, mortality from haemorrhagic shock has not declined over the previous two decades. A proportion of shocked trauma patients may experience a deficiency of cortisol relative to the severity of their injury. The benefit of exogenous steroid administration in patients suffering haemorrhagic shock as a result of injury is unclear. A systematic review of four databases  was undertaken. Inclusion and exclusion criteria were pre‐determined and two reviewers independently screened the articles with disagreements arbitrated by a third reviewer. The primary outcome variable was 28‐day mortality. Quality of studies were assessed using the Cochrane‐risk‐of‐bias (RoB 2) tool. Of the 2919 studies yielded by the search strategy, 1274 duplicates were removed and 1645 screened on title and abstract. After the full text of 33 studies were assessed, two articles were included. Both studies were over 30 years old with small numbers of participants and with primary outcomes not including mortality. Of the data available, no statistically significant difference in mortality was detected. Hospital length of stay, reversal of shock or adverse events were not reported. Both studies were at risk of bias. There are no high quality or recent studies in the English literature investigating the use of steroids for haemorrhagic shocked trauma patients. PROSPERO: CRD42021239656. Earlysteroid administration for traumatic haemorrhagic shock: A systematic review Observational data suggests a proportion of shocked trauma patients may experience a deficiency of cortisol relative to the severity of their injury.Our systematic review of the literature identified only two small studies, both over 30 years old at high risk of bias. No difference in mortality was detected, length of stay, reversal of shock and adverse events were not reported.Our review revealed no evidence to guide steroid use in the setting of traumatic hemorrhagic shock. Further prospective studies to gauge benefit from steroid use in this cohort is warranted.Haemorrhagic shock is a life‐threatening condition of inadequate organ perfusion as a result of circulatory failure secondary to blood loss. Traumatic injury results in an estimated 60 000 deaths per year in the USA and 1.5 million deaths worldwide.Research in the mid‐1970s highlighted the importance of timely haemostatic and resuscitative interventions.Despite this, mortality rates among patients who present with shock have remained static since 2000.Profound hypovolemia and shock results in tissue hypoperfusion, neuroendocrine stress response and activation of the coagulation cascade producing an inflammatory pathway referred to as the systemic inflammatory response syndrome (SIRS). This causes cellular and organ damage and contributes to ongoing haemodynamic instability.Prospective observational studies have demonstrated that a significant proportion of haemorrhagic shocked trauma patients experience a deficiency of cortisol relative to the severity of their injury early in their resuscitation.Numerous animal studies over the last century have established the importance of cortisol in the body's response to stress and haemorrhage.Available experimental and observational data suggest a possible cortisol deficiency and potential utility of exogenous steroids in patients suffering traumatic haemorrhagic shock. Owing to the prevalence of traumatic haemorrhagic shock, benefit from a cheap and available drug would have a large impact. There appear to have been no published reviews to date examining the effectiveness of early administration of steroids to traumatic haemorrhagic shock patients. This systematic review was undertaken to determine the level of evidence supporting early steroid administration for traumatic haemorrhagic shock and its effect on mortality.This systematic review was performed as recommended in the Preferred Reporting Items for Systematic Review and Meta‐Analyses statement.Four electronic databases  were searched systematically from inception to 2 March 2021. A preliminary search was conducted of Medline and Embase and analysis of text words and subject headings was performed to develop the final search strategy. In addition, reference lists of included articles and relevant reviews were manually searched for appropriate studies. A detailed description of the search strategy including all the search terms is included in Only human studies and studies published in English were included. Papers with study populations  of subjects with traumatic haemorrhagic shock to whom steroids were administered in the early phase were included. The early phase was defined as <24 h from time of injury or outlined as the ‘resuscitative phase’ by the paper's authors. Definition of shock was at the discretion of the authors of the individual trials. Administration of any type or dose of intravenous corticosteroids including dexamethasone, prednisolone or methylprednisolone was accepted. Paediatric studies, reports on patients with pre‐existing adrenal impairment, studies in which relevant outcomes were not reported and studies in which only measurements of cortisol levels were performed rather than the administration of steroids were excluded.Randomised controlled trials, prospective and retrospective observational studies as well as case series were included. Reviews, including systematic reviews and meta‐analyses were excluded as well as opinion pieces.Two reviewers (JPH and MEJ) independently screened the titles and abstracts of the studies to assess each article's suitability for inclusion. Any inconsistencies in screening were discussed and resolved in consultation with a third reviewer (KJ). Reference lists of relevant reviews and included full text studies were screened for suitable studies.The primary outcome measure was 28‐day mortality. Shorter term mortality was accepted if 28‐day mortality was not available. Secondary outcomes measured were early reversal of shock at Day 2 and reversal of shock at Day 7, time to shock reversal, length of stay in hospital and ICU, 90‐day mortality and ICU and in‐hospital mortality. Adverse outcomes of administration of steroids included gastrointestinal bleeding, hypernatraemia, sepsis/infections and hyperglycaemia. All studies meeting inclusion criteria were included in analysis. Study characteristics were entered into tables to compare against planned groups for each synthesis.vs low dose steroids; (ii) penetrating vs blunt trauma; (iii) duration of treatment: short ≤4 days vs long >4 days; and (iv) the type of steroid used.Subgroups included were (i) high dose Data were collected independently by two reviewers (JPH and MEJ) and any inconsistencies were discussed and reviewed in conjunction with a third reviewer (KJ).P‐value of <0.05 was used for statistical significance.Dichotomous variables were planned to be analysed using the Mantel–Haenszel method and expressed as risk ratios (RRs). Continuous variables were to be analysed using the inverse variance random‐effects model and expressed as mean differences. A Heterogeneity was to be assessed using the Paule and Mandel estimation method as well as visual inspection of forest plots.RoB 2: Revised Cochrane Risk of Bias Assessment ToolGrading of recommendations, assessment, development and evaluations (GRADE) was used to assess the quality of evidence for each outcome. Risk of bias in individual studies, publication bias, precision, consistency and directness were assessed to give an overall confidence rating of effect estimates for each outcome.The search strategy yielded 2914 records. An additional five records were identified through reference lists of relevant reviews and included studies. One thousand two hundred and seventy‐four duplicates were removed. One thousand six hundred and forty‐five studies were screened on title and abstract by the two reviewers. Thirty‐three papers were identified for assessment of full text for eligibility resulting in inclusion of two randomised controlled trials . In this period, an average of 13.1 units of blood, 11.7 L of balanced salt solution and 800 ml of FFP were transfused in similar quantities between the two groups. A further 15 mg/kg of methylprednisolone was provided to the intervention group over the next 3 days.P < 0.10, χ2 = 3.6 as reported in trial). Ventilator support was required for 5.1 days in the steroid‐supplemented group vs 3.0 in non‐supplemented group (P < 0.10)The primary outcome for the study were measures of pulmonary function. Differences in mortality was a secondary outcome. There was no significant mortality difference  looking at mortality revealed an overall ‘high risk of bias’. This arose from Domain 1 (randomisation process) relating to the allocation of patients via their patient identifier number and the lack of concealment associated with this. ‘Some risk of bias’ was also identified in Domain 5 (selection bias of reported result) in relation to the lack of clarity regarding when mortality was measured. Domains 2, 3 and 4 returned a low risk of bias result .vs control group. 1 mg/kg of dexamethasone was provided to patients in the experimental group, the specific time or method of infusion was not reported.In the second paper published in 1970, Schumer and Nyhus from the Department of Surgery, University of Illinois College of Medicine, randomised 50 haemorrhagic shocked trauma patients not responding to volume replacement with blood, Ringer's solution and sodium bicarbonate to receive supplemental dexamethasone or saline solution. It is not explicitly stated how many patients were in the experimental vs 60% in the control group was reported, the time point of determination of mortality was not mentioned in the text. Statistical significance was not reported. However, using the data provided the χ2 statistic is 2.38 (P = 0.12). A ‘biochemical index’ consisting of the mean values of lactate, phosphate and serum amino acids returned to baseline 75 min earlier in steroid treated patients compared to the controls. Statistical significance related to this was not reportedA survival rate of 80% in the steroid treated group RoB 2 reviewing mortality demonstrated an overall ‘some risk of bias’ result. This arose from Domain 1 (randomisation process) because of the lack of information pertaining to the randomisation process and baseline characteristics of the patients. ‘Some risk of bias’ was also found in relation to Domain 5 (selection bias of reported result) in relation to the lack of clarity regarding when mortality was measured. Domains 2, 3, 4 returned ‘low risk of bias’ results .As a result of the limited number of studies identified, and a lack of clinically or statistical homogeneity, a pooled analysis was not undertaken.GRADE assessment performed on the studies indicated a very low certainty in the evidence found Table .The effectiveness of early steroids during the management of traumatic haemorrhagic shock after trauma was assessed by two trials, both of which were old and missing key variables regarding the age of subjects, severity of trauma and nature of injuries. There was no reported statistically significant association with mortality, although both studies involved small numbers and mortality was not a primary outcome.Consistent with trends in shock management at the time of publications,Meta‐analyses performed by the Society of Critical Care Medicine and European Society of Intensive Care Medicine examined 12 000 trauma patients provided with supplemental steroids of any dose. No statistically significant benefit or harm was found among the 12 000 patients included. No difference was found when stratified into low dose or high dose corticosteroid. No increased risk of superinfection or gastrointestinal bleeding was identified.et al. provided low dose hydrocortisone or placebo within 36 h to ICU trauma patients, not necessarily haemorrhagic shock, expected to be mechanically ventilated for >48 h.The HYPOLYTE study by Roquilly et al. compared a prospective cohort of ICU trauma patients provided with steroids with a retrospective control cohort . 45% of patients were hypotensive but this subgroup was not analysed separately for outcomes.Similarly, Chaari et al. conducted a prospective observational study measuring the admission cortisol of 59 consecutive patients presenting to their trauma centre in the USA with haemorrhagic shock.n = 10) of patients had what they defined as severe hyper‐acute adrenal insufficiency (SHAI) (<10 μg/dl) and 86% (n = 51) met their definition for relative hyper‐acute adrenal insufficiency (RHAI) (<25 μg/dl). 46 (78%) of patients had a time of injury available and blood was drawn an average of 56.6 (±26.3) min from this injury.P = 0.001) indicating each 1 μg/dl decrease in cortisol level in this cohort was associated with a 23% increase in mortality within 24 h.The rationale behind providing supplemental steroids to shocked patients comes from data suggesting that critical illness induces a state of insufficient cortisol response relative to the insult. In the traumatic haemorrhagic shock setting this has been examined in a small number of prospective and retrospective papers. Stein et al. tracked the levels of cortisol and other pituitary hormones of 42 haemorrhagic shock trauma patients at admission and over the first few days of their hospitalisation.et al. their population had an incidence of 19% SHAI and 76.2% RHAI. Non‐survivors were found to have lower admission cortisol levels when compared with survivors. Interestingly, survivor cortisol levels increased throughout their admission  whereas non‐survivors cortisol decreased significantly over time, perhaps suggesting a decompensated response .In a similar fashion, Joseph et al. examined cortisol and ACTH levels but across the spectrum of trauma presentations.Likewise, Barton et al. assessed a variety of vasoactive mediators, including cortisol among trauma patients presenting to their facility with a systolic blood pressure <90.et al. observed the cortisol level of 15 subjects presenting with haemorrhagic shock whom had their cortisol measured.Similarly, Cohn Although there appears to be a reasonable prevalence of relative adrenal insufficiency (RAI) in early haemorrhagic shock trauma patients, the pathophysiology of cortisol differs in the acute inflammatory state. Normally free cortisol acts as the active glucocorticoid in the body but only represents 5–10% of total body cortisol; with the remainder bound mostly to corticotropin binding globulin (CBG) and to a lesser extent albumin.As a result of these complicating factors, there is no consensus on diagnostic levels for a RAI. Studies use a variety of thresholds including a baseline cortisol <10/15/25 μg/dl or a decreased response to a synthetic ACTH stimulation test. This makes the interpretation of comparative results difficult.Injury resulting in haemorrhagic shock is a leading cause of mortality globally as well as economic burden through medical costs and loss of productivity.This review revealed no recent or high‐quality studies to guide the use of early steroids in traumatic haemorrhagic shock patients. It is known that haemorrhagic shocked trauma patients experience ongoing haemodynamic instability related to SIRS. Although estimation of active cortisol in the acute state is difficult, there is evidence to suggest that a proportion of trauma patients, perhaps related to uncharacterised phenotypic variations, experience a deficiency in endogenous glucocorticoid in response to the severity of injury and the presence of haemorrhagic shock.This review was conducted in accordance with the PRISMA statement. A research librarian was consulted to assist with developing the search strategy  and a brA small number of studies met the inclusion criteria highlighting the gap in the literature regarding steroid use in traumatic haemorrhagic shock patients. Identified studies were both over 30 years old and utilised high dose steroids and resuscitation strategies current at the time of publication but no longer in practice, making them of little relevance to present day management. As a result of the limited number of included studies, a pooled analysis was not undertaken.This review of over 2900 studies yielded only two studies, both over 30 years old with administration of very high steroid doses, small numbers of participants and incomplete results. Both were at risk of bias and of very low quality. As such, among haemorrhagic shocked adult trauma subjects there has been no high quality or recent studies examining the effect on mortality of early steroid supplementation. Given that steroids are cheap, ubiquitous and simple to administer and the magnitude of patients affected by traumatic haemorrhagic shock each year, further prospective studies to gauge benefit from steroid use in this cohort is warranted.Appendix S1. Database search strategy – MEDLINE.Click here for additional data file.Appendix S2. List of citations identified on title and abstract and reason for exclusion or inclusion.Click here for additional data file.Appendix S3. RoB 2 Lucas and Ledgerwood – Mortality.Click here for additional data file.Appendix S4. RoB 2 Schumer and Nyhus ‐ Mortality.Click here for additional data file.Appendix S5. PRISMA checklist.Click here for additional data file.


To the Editor,We welcome and appreciate the comments made by Mei and colleagues about our recent publication, “Epidemiology of heart failure hospitalization in patients with stable atherothrombotic disease: Insights from the TRA 2°P‐TIMI 50 trial.” In this article, we show that the risk for hospitalization for heart failure (HHF) among patients with stable atherosclerosis is heterogeneous—with the highest risk in those with pre‐existing heart failure , polyvascular disease , and type 2 diabetes .Mei and colleagues raise the concern that we may have overestimated the impact of pre‐existing heart failure on HHF in patients with stable atherosclerosis. The stated basis for their concern is that in a propensity matched analysis of 2,768 patients hospitalized for decompensated heart failure, Malik et alAlthough these analyses both support the prognostic relevance of prior heart failure when estimating risk of future adverse heart failure events, the difference in magnitude is not unexpected given the different populations. In the study by Malik et al,Another difference between the studies is ascertainment and categorization of endpoints. In Malik and colleagues' propensity‐matched cohort study, HHF incidence was ascertained from Medicare claims. Billing codes have the potential for inflating event rates and diminishing specificity while adjudicated outcomes may reduce event rates and increase specificity. In fact, in our trial‐based analysis, despite a larger (~8‐fold) gradient of HHF risk, patients with pre‐existing heart failure actually had a lower cumulative HHF incidence in our study (3.8%/year) than was observed by Malik and colleagues among those with no HHF in the preceding 6 months .Mei and colleagues further propose that the value of pre‐existing heart failure in predicting incident HHF in our study may be confounded by the relatively high prevalence of atrial fibrillation among patients with heart failure. However, the number of patients with atrial fibrillation in the analysis was negligible, given that anticoagulation was an exclusion criterion for the TRA 2°P‐TIMI 50 trial.Lastly, Mei and colleagues point out that the reported null effect of vorapaxar on HHF incidence comes solely from a Cox proportional hazards model of time to first HHF, excluding the 116 recurrent HHF that occurred during 3‐year follow‐up. It is important to note that the allocation of vorapaxar in the analysis was randomized, and despite this, there was no numerical trend favoring vorapaxar over placebo in reducing the risk of first HHF . Since first and recurrent heart failure events are related, a total events analysis would be unlikely to produce a change of the magnitude needed to show a benefit. With regard to the use of antithrombotic therapy in patients with heart failure, the 2021 European Society of Cardiology (ESC) Guidelines cite a subgroup analysis of the COMPASS trial which showed that low‐dose rivaroxaban has consistent benefit with respect to reducing MACE in patients with PAD and/or CAD and concomitant HFpEF or HFmrEF.


Redo cardiac surgery can present a unique set of challenges even to the experienced surgeon. Although outcomes have steadily improved in the modern era; if an intraoperative adverse event occurs, there is a 5% incidence of mortality and 19% incidence of myocardial infarction, stroke or death. Overall, the modern incidence of mortality at reoperation varies but be segregated into low and higher risk cohorts depending on the planning computed tomography imaging and risk to substernal structures on re‐entry. Patients with ascending aortic or root pseudoaneurysms represent a particularly difficult subset of high‐risk patients requiring reoperative cardiac surgery due to the danger of exsanguination and air embolization. The gold standard for management of such cases remains the use of deep hypothermic circulatory arrest (DHCA) to achieve safe re‐entry in such cases however this can result in unpredictable DHCA duration depending on the degree of pericardial adhesions. We report a case of aortic pseudoaneurysm in a patient with patent coronary grafts managed using an endoballoon precisely positioned relative to the proximal anastomoses resulting in a safe surgical re‐entry and shorter DHCA time. He had undergone coronary artery bypass grafting at another center 5 months prior with left internal mammary artery to left anterior descending artery (LIMA‐LAD), and saphenous vein grafts to posterior descending artery and ramus intermedius complicated by left arm ischemia requiring angioplasty. He had represented at an interval with progressive dizziness, fatigue, and lightheadedness. Computed tomography (CT) imaging revealed an aortic pseudoaneurysm at the original aortic cannulation site with an ostium of 9 × 7 mm that was compressing 50% of the main pulmonary artery Figure .1, 2In addition to his remaining workup, an interval CT 12 days later demonstrated an increase in the size of the pseudoaneurysm and surrounding complex fluid collection in the anterior mediastinum. Infectious etiology could not be out‐ruled  Figure .A percutaneous retrograde cardioplegia catheter was advanced under TEE guidance into the coronary sinus. Cardiopulmonary bypass was commenced and upon resternotomy bleeding was encountered from the pseudoaneurysm. The endoballoon was inflated above the proximal coronary anastomoses to occlude the aorta and control the bleeding. The endoballoon also served to deliver antegrade cardioplegia. In view of the patent LIMA‐LAD graft, continuous retrograde cardioplegia and systemic hyperkalemia also instituted and cardioplegic arrest was achieved; during this period the endoballoon served as a vent. Further dissection was carried out revealing a 1 cm defect in the distal ascending aorta at the previous cannulation site Figure .Once the patient was adequately cooled, deep hypothermic circulatory arrest (DHCA) was instituted and the endoballoon deflated. A bovine pericardial patch was sewn into the defect, the aorta and heart de‐aired, systemic flow restored, and the patient rewarmed. Endoballoon inflation time was 32 min with DHCA of only 8 min. Postprocedural echo demonstrated normal biventricular function and the patient was transferred to intensive care in a stable condition. Post procedural CT demonstrated an excellent result with complete resolution of the pseudoaneurysm Figure .2The development of minimally invasive mitral surgical approaches and the concomitant anesthetic upskilling that has been required has resulted in a broader range of tools at the disposal of cardiac surgical teams approaching cases such as these. Advantages of using the endoballoon in this setting are shorter DHCA time, excellent myocardial protection and complete decompression of the left ventricle during re‐entry. Whilst this approach has been reported in several other publications, this case is unique due to the added complication of patent coronary grafts


Typical signs of heart failure (HF), like increased cardiothoracic ratio (CTR) and pleural effusion, can be seen on X‐ray. Artificial Intelligence (AI) can help in the early and quicker diagnosis of HF.The study's goal was to demonstrate that the AI interpretation of chest X‐rays can assist the clinician in diagnosing HF.Patients older than 45 years were included in the study. The study analyzed 10 100 deidentified outpatient chest X‐rays by AI algorithm. The AI‐generated report was later verified by an independent radiologist. Patients with CTR > 0.5 and pleural effusion were marked as potential HF. Flagged patients underwent confirmatory tests, and those labeled as negative also underwent further investigations to rule out HF.Out of 10 100, the AI algorithm detected 183 (1.8%) patients with increased CTR and pleural effusion on chest X‐rays. One hundred and six out of 183 underwent diagnostic tests. Eighty‐two (77%) out of 106 were diagnosed with HF according to current guidelines. From the remaining 9917 patients, 106 patients were randomly selected. Nine (8%) out of them were diagnosed with HF. The positive predictive value of AI for diagnosing HF is 77%, and the negative predictive value is 91%. More than half (54.9%) of newly diagnosed patients had HF with preserved ejection fraction.HF is a risky condition with nonspecific symptoms that are difficult to diagnose, especially in the early stages. Using AI assistance for X‐ray interpretation can be helpful for early diagnosis of HF especially HF with preserved ejection fraction. Artificial Intelligence (AI) may help in the early and quicker diagnosis of heart failure (HF). Patients with cardiothoracic ratio (CTR) >0.5 and pleural effusion on chest X‐rays were marked as potential HF by AI. Potential HF patients underwent diagnostic tests such as natriuretic peptides and echocardiography. AI algorithm detected 183 (1.8%) patients with increased CTR and pleural effusion on chest X‐rays of 10,100 patients. 77% of AI‐positive patients were diagnosed with HF. Eight percent of AI‐negative patients were diagnosed with HF. The positive predictive value of AI for diagnosing HF is 77%, and the negative predictive value is 91%. The majority of newly diagnosed HF patients had non‐reduced ejection fraction. Due to the increased survival of coronary vascular disease patients, the prevalence of HF is rising worldwide.The mortality of HF patients remains high and can range from 5% to 15%, even during hospitalization.Patients of HF often present with dyspnea as one of the chief complaints. A chest X‐ray is the first modality of imaging as this is low‐cost, noninvasive, and helps differentiate between cardiac and pulmonary reasons of dyspnea.Deep Learning has been used to help assess HF using different types of clinical information.A rapid and accurate HF diagnosis is of utmost importance to decrease the patient's mortality and reduce the medical expenditure. Our project aims to identify potential HF patients by detecting increased CTR and pleural effusion on their chest X‐rays with the help of AI scanning and thus assist in the quicker diagnosis of HF.2The study was conducted as a single‐center prospective study where X‐rays of eligible patients were analyzed from January to September 2021. Ethics approval (2021/767) was obtained before the initiation of the study from Mersin University Ethics Committee members. During the study period, the AI and expert radiologists analyzed chest X‐rays of subjects admitted to the outpatient departments of Mersin University Medical Faculty Hospital between January 1, 2021, and September 30, 2021. Subjects older than 45 years were included in the study. The patients who were admitted to outpatient clinics of cardiology and cardiovascular surgery were excluded. The patients who were admitted to emergency department, hospitalized patients, and patients with history of HF were excluded from the study. An AI algorithm analyzed the chest X‐rays of selected subjects. AI positive had findings of increased CTR and pleural effusion. Subjects with increased CTR (>0.5) and bilateral pleural effusion were marked as potential HF patients on their X‐rays. These patients were then invited to the cardiology outpatient department for further, definitive HF diagnostic tests to confirm the diagnosis of HF. They underwent physical examination, natriuretic peptides, and transthoracic echocardiography tests in addition to initial Chest X‐rays. The diagnosis of HF were done according to the “2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic HF.Subjects (randomly sampled) who did not show increased CTR and pleural effusion on their chest X‐rays were also invited to rule out HF diagnosis in them. We used qXR (Qure.ai) for chest X‐rays analysis of selected patients. First, all the DICOM  images of X‐ray images were deidentified. Then, these deidentified DICOM images were imported into the system to be analyzed by qXR. These deidentified X‐rays were then analyzed by an AI algorithm (qXR) and were later verified by an independent radiologist from the hospital with experience in thoracic imaging. A final report was generated for each case. Further statistical analyses were done based on the radiologist's report and qXR findings.The qXR has been trained on 2.3 million+ chest X‐rays. A Deep Learning model called convolutional neural networks (CNNs) was used to develop qXR.2.1p < .05 was accepted as statistically significant from a statistical perspective.Statistical analysis was performed using IBM SPSS statistics version 21 (IBM Corporation). Continuous data are presented as mean or median for normal, nonnormally distributed variables, respectively, and categorical data are shown as numbers (percentages). To evaluate the diagnostic performance of AI for HF, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio, negative likelihood ratio, accuracy, and diagnostic odds ratio (OR) analysis were done with 95% confidence Interval. A 3Based on the eligibility criteria, anonymous chest X‐rays of 10 100 patients were uploaded on the qure.ai platform. Figure 2, and as a result, serum creatinine in flagged patients was higher at 1.28 as compared to only 0.81 in nonflagged patients. Flagged patients were slightly older than nonflagged patients and a had higher percentage of coronary artery disease, previous myocardial infarction, diabetes, and hypertension.The baseline characteristics of these patients were summarized in Table An accuracy of 84% was found in diagnosing HF using the chest X‐ray images that AI analyzed. The diagnostic value of AI for HF is summarized in Table 4HF is a complex, risky cardiac condition that is difficult to identify in the initial stages. In addition, HF presents nonspecific symptoms like cough and dyspnea that are confused with pulmonary disorders, thus causing a delay in diagnosis and increased morbidity. Among the three types of HF, HFpEF  is the most difficult to diagnose due to the lack of apparent signs and symptoms of HF.HF due to reduced EF is easier to diagnose as the symptoms are more apparent and the patient presents earlier. However, it is challenging to analyze, especially in outpatient settings, in the absence of overt symptoms.There are invasive tests like natriuretic peptides that can indicate HF. Some noninvasive diagnostic modalities like echocardiography and exercise stress tests also help diagnose. However, these expensive tests are difficult to perform in multiple settings, especially in low‐resource or nontertiary setups, and are not widely available.X‐ray is a noninvasive diagnostic modality that is widely available worldwide and is low‐cost. X‐rays are the first imaging modality that is done when patients present with symptoms of HF to differentiate the cardiac from the pulmonary cause. There are HF signs that can be seen on X Rays like increased CTR, Kerley B lines, and pleural effusion that can be subtle, especially in HFpEF, and are difficult to identify on an X‐ray. However, with proper training, an AI algorithm can pick these signs and help in identifying potential HF patients early in the disease state. The use of AI can assist with the shortage of trained clinicians who can diagnose HF on X‐rays in low‐resource and remote settings.ART‐IN‐HF project is the pioneering initiative that used chest X‐ray analysis by AI for the early diagnosis of HF. This was done by detecting increased CTR and pleural effusion together on the X‐rays of potential HF cases. Diagnostic accuracy of X‐ray analysis by AI for HF in patients with pleural effusion and increased CTR was found in 183 patients (1.8%). AI will be helpful for detecting HF using chest X‐ray scans in undiagnosed HF patients, especially for difficult‐to‐diagnose HFpEF patients. Most newly diagnosed HF patients (73.2%) have HF with nonreduced EF. Data suggests that the undiagnosed HF patients in the population likely have HF with nonreduced HF.Although it is accepted that the proportion of patients with HFpEF is equal to that of HFrEF , in the European Society of Cardiology Heart Failure Long‐Term Registry, the ratio of patients with HFpEF is 16%, and the proportion of patients with HFmrEF was 24.2%. SELFIE‐TRAn increase in awareness of HF without reduced LVEF can be beneficial for both patients and physicians. This will help in early diagnosis and initiation of treatment, especially in patients who have risk factors for developing HF . In addition, early diagnosis of HF will help in reducing morbidity and mortality of patients as well as cost savings by reducing complications. This study demonstrates that AI assistance can be helpful for the early detection of HF using X‐rays, even in non‐symptomatic or minimally symptomatic patients.Our study is one of the first attempts to use deep learning to read X‐rays and assist in the diagnosis of potential HF cases. Our study adds to the evidence and demonstrates that AI can be used for the early detection of HF cases using X‐rays, even in non‐symptomatic or minimally symptomatic patients. The promising results of this study are encouraging and warrant a multicentre prospective clinical trial to learn more about the impact of AI on treatment outcomes and to create a new protocol for screening of HF using AI.4.1The study was a single‐site study; however, a multisite study might be more generalizable. The inclusion criteria included only 45 years and older. However, HF can occur in younger patients also. The proportion of participants who underwent confirmatory tests could have been larger, which could have shown a much greater number of HF cases. Study results being at the tertiary center might not be applicable at the smaller or nontertiary centre. The study population was mainly from a particular geographic location, that might have influenced the final results.4.2Diagnosis of HF for clinicians is not easy. Diagnosis becomes even more difficult without the provision of tests like proBNP. HF signs can be picked up on chest X‐rays. The use of AI has been on the rise in the field of cardiology. This study demonstrated that AI could help in the diagnosis of HF. There are many potential clinical implications of this study. This study opens many opportunities for generating newer medical knowledge where the early changes in HF can be tracked through AI by sequential X‐ray over time and can play a vital role in newer clinical evidence generation.The discovery of newer cases early in the disease process might result in a change in documented prevalence of HFpEF in the general population. This potential change in prevalence might result in a change in the guidelines for screening and management protocols of HF.Using AI in HF diagnosis will also result in better patient care as more HFpEF patients can be identified earlier in the process and, appropriate clinical care can be initiated before the onset of symptoms. This will reduce chances of complications in patients, the morbidity and burden of HF disease in the population.Early diagnosis of HFpEF with other comorbidities will help identify patients who need active interventions like cardiac procedures. This might result in newer modalities of treatment and surgical intervention for patients with specific comorbidities in addition to HF.This study can become a catalyst for more research in early diagnosis of HF using machine learning or AI. In addition, this can become a precursor of multicentre clinical trials where even bigger numbers of patients with multiple comorbidities might be part of the trial. Such trials can generate medical evidence that can change the guidelines of HF management. These can also be instrumental in newer specific scientific evidence for the discovery of newer drugs or newer surgical modalities to manage HF.The authors declare no conflict of interest.Supplement Figure 1. The comparison of subjects according to AI flagged or non‐flagged.Click here for additional data file.Supporting information.Click here for additional data file.


Young adulthood is a key developmental period for understanding outcomes of childhood onset attention‐deficit/hyperactivity disorder (ADHD) and autism. Measurement of functional impairment and quality of life (QoL) can provide important information on the real‐life challenges associated with these conditions. Event‐related potential (ERP) measures from the continuous performance task (CPT) have long been identified as altered in ADHD and autism but the role of these functions in the aetiological pathway to the disorders and associated impact on quality of life in young adulthood is unknown.We investigated the relationships between ADHD and autism, functional impairment, quality of life, and ERP measures from the cued CPT (CPT‐OX) in a young adult twin sample (566 participants aged 22.43 ± 0.96 years old).We observed significant phenotypic correlations between ADHD/autism and lower quality of life with specific genetic overlap between ADHD and physical health, psychological, and environmental aspects. We found significant phenotypic and genetic correlations between ADHD and functional impairment in all domains, as well as between autism and impairment in social functioning and lower impairment in risk‐taking. Both ADHD and autism were associated with attenuated amplitude of inhibitory and proactive control ERPs, with large genetic contributions to the overlap. We also found significant phenotypic correlations between these ERP measures and Weiss Functional Impairment Rating Scale (WFIRS) and QoL.This is the first study to investigate the phenotypic and genetic relationships between ADHD and autism, functional impairment, quality of life and ERP measures in young adulthood. Our findings could represent a step towards identifying ERP measures that are related to behaviour in the absence of overt symptoms. Young adulthood (ages 18–25) is a key developmental period for understanding adult outcomes of childhood onset ADHD and autism. We investigated the relationships between ADHD and autism, functional impairment, quality of life, and event‐related potentials from continuous performance task in a young adult twin sample. We observed significant associations accompanied with significant genetic and environmental overlaps in many cases. First study to investigate the phenotypic and genetic relationships between attention‐deficit/hyperactivity disorder (ADHD) and autism, functional impairment, quality of life (QoL), and event‐related potentials (ERPs) in a young adult twin sample.Decreased QoL in both ADHD and autism. ADHD is associated with increased functional impairment in all domains while autism is associated with higher/lower impairment in social‐functioning/risk‐taking.Both ADHD and autism are associated with abnormal ERPs time‐locked to inhibitory and cue stimuli with large genetic overlap in some. Significant associations between these ERP measures and functional impairment and QoL.The window in development between adolescence and adulthood –young adulthood (ages 18–25) – is critical for understanding adult outcomes of childhood onset ADHD and autism  and person‐first language  when referring to the individuals with high traits on these conditions.Full ethical approval for the study was received from King's College London Psychiatry, Nursing and Midwifery Research Ethics Subcommittee (RESCMR‐16/17‐2673). Data were collected as part of the Individual Differences in EEG in young Adults Study (IDEAS). IDEAS participants were all recruited from the Twins Early Development Study (TEDS), a community sample of over 16,000 twin pairs born in England and Wales between 1994 and 1996 , it was not intended to be a whole community or community representative sample. The sample consisted of 556 participants  with an average age of 22.43 ± 0.96 years (119 Monozygotic (MZ) and 164 Dizygotic (DZ) pairs) : a semi‐structured interview conducted by a trained investigator to assess ADHD symptoms : a semi‐structured assessment allowing observations of social and communication behaviours relevant to the diagnosis of autism. We used module four of ADOS‐2 (designed for adolescents and adults with fluent speech) : a self‐report scale examining adult ADHD‐related impairment with 70 items covering seven domains of dysfunction: family relations, work adjustments, school performance, life skills, self‐concept, social functioning, and risk‐taking. It also provides two metrics of overall impairment: the total mean  and domain mean  : a self‐report questionnaire to assess the quality of life in four domains: physical health, psychological, social relationships and environmental  system . EEGLAB  were removed. An EEGLAB study was then created from these epochs and dipoles located outside the brain or with higher than 15% residual variance were rejected.EEG data were downsampled to 256 Hz, bad EEG channels/time intervals were removed (see Supporting Information for details) and average reference was applied. Independent component analysis (ICA) was applied to each individual recording using Adaptive Mixture ICA (AMICA)  toolbox , common environment variance (c2), and unique environment variance and measurement error (e2). Considering most genetic variance is additive  and dominance (d2) genetics separately, we only used ACE models which will mean dominance genetic variance will go in a2 and therefore a2 reflects broad sense heritability.Twin modelling is based on fitting a genetic model that explains differential correlations observed in twin data by considering the MZ twins share 100% and DZ twins share 50% of their genetic influences while MZ and DZ twins equally share environmental factors  in the analyses. If these are diagnostic measures and only certain extreme groups are included , then in addition we also need to fix the model parameters. We fixed the thresholds, set to the population prevalence of 4% for ADHD  relationships. In these models, age and sex were accounted for as covariates and a random intercept was used to control for twin relatedness . The genetic contribution to this correlation was also significant (64%). While the total phenotypic correlation between autism and risk‐taking was not statistically significant, the genetic contribution was statistically significant (−0.20) Table . This isc2) contributions were highest for FA6 (0.29) and FA2 (0.19)  Figure . While t32) between social QoL and FA2 and FA6 as well as work adjustments and FA1 and FA5 suggested considerable association between ERP factors and these WFIRS and QoL measures independent of ADHD and autism (Table Work adjustment (WFIRS) was phenotypically associated with a broad representation of ERP factors: FA1 (−0.14), FA3 (−0.13) and FA5 (0.12); however, the contribution of genetics to these relationships were not statistically significant. Social relationships (QoL) showed significant negative phenotypic correlations with FA2 (−0.12) and FA6 (−0.10), with significant common environment contributions for FA6 at −0.22 (Rc = 1.00). Social functioning (WFIRS) showed a different pattern of results: a small yet significant relationship emerged between FA4 and social functioning (0.12) , quality of life (QoL), and ERP measures (CPT‐OX task) in 283 young adult twin pairs. Significant phenotypic correlations emerged between both ADHD and autism and QoL in all four domains of physical health, psychological, social relationships, and environment. The association of ADHD and autism diagnosis with lower QoL agrees with previous studies in both autism . The negative loading for the amplitude of cue N2 and the positive loading for cue P3 amplitude at the parietal‐occipital source domain Figure . The enhDespite observing significant associations between ERP measures and ADHD and autism, the effect sizes are small which may limit their predictive value. However, these correlations, remain important despite their small size because they contribute to the understanding of aetiological mechanisms of these disorders. Both ADHD and autism are likely to be determined by numerous factors, each of which makes only a small contribution, which therefore may result in small effect sizes. Considering this, we believe none of these measures will be sufficient for diagnosis of ADHD and autism but could well be considered as aetiologically important in the development of the disorders alongside other measures.A central aim of the study was to investigate associations between ERP indices of the CPT‐OX and WFIRS and QoL. While the CPT‐OX ERPs were broadly related to functional impairment and QoL, evidence for genetic/environmental overlap was limited. Impairment in work adjustments was phenotypically associated with the greatest number of ERP factors  were significant. For example, despite significant phenotypic correlations and substantial genetic associations between autism and physical health (94% and a significant Ra = −0.28) and psychological (85%) QoL, the genetic contributions were not statistically significant, which may be due to the sample being underpowered or it is also possible that this is due to lack of a true effect. The relatively small sample size for a twin study required reduction of the number of tests performed. To find a balance between potential type I and type II errors, variables were preselected for investigation in the twin modelling using multilevel mixed effects models testing for phenotypic relationships (independent of twin relatedness). However, the selection of variables may necessarily exclude information about additional alterations in brain function in the conditions. Since the study sample was enriched for high levels of autistic and/or ADHD traits, we fixed prevalence thresholds and heritability to population values based on representative twin samples. As the estimates are not from the exact same population, but from similar populations, there may be minor influences on the model estimates.While the WFIRS was originally proposed to measure functional impairment for adults with ADHD, which might be used to explain the lack of associations with autism for some domains, this is unlikely given the clear relevance of WFIRS domains for autism. We were unable to investigate comorbid ADHD and autism as a separate group due to the low number of cases with comorbid diagnosis in our sample. It would be of interest to examine the comorbid diagnosis in young adulthood in the future given the evidence for an additive model of cognitive impairments for the comorbid group in childhood .Supporting Information S1Click here for additional data file.


Whereas high‐level evidence exists on chronic neuromodulatory effects of different brain stimulation approaches in reducing seizure frequency, evidence for acute antiseizure effects of electrical brain stimulation during seizures is sparse. As part of an ongoing trial, we implanted a patient with a novel focal cortex stimulation (FCS) device with a Laplacian electrode placed over a precentral focal cortical dysplasia. The baseline seizure frequency was 125 per month, consisting of (i) focal aware sensory seizures that invariably progressed to uni‐ or bilateral tonic contraction and clonic jerking, and (ii) primary motor seizures. Besides an overall reduction in seizure frequency, on‐demand stimulation had an immediate effect on seizures with a sensory phase, whereby 63%‐86% of these seizures were terminated by ictal stimulation. These observations provide the first evidence that ictal self‐triggered transcranial focal cortex stimulation can significantly interfere with the progression of seizure semiology. At the time of enrolment, the patient had prolonged focal aware sensory seizures that lasted several minutes and regularly progressed to focal motor seizures, often resulting in postural instability and falls. Based on his refractoriness to 13 previously administered antiseizure medications, the patient underwent both non‐invasive and invasive presurgical monitoring. Scalp EEG recordings showed polyspike discharges over the right precentral region, concordant with MR imaging suggestive of a bottom‐of‐sulcus type II focal cortical dysplasia  and thalamic deep brain stimulation (DBS) are thought to induce network neuromodulation by way of intermittent interictal effects at sites distant to the epileptic focus. In this settings, the efficacy of stimulation increases over periods of several months to years when identical stimuli are applied, suggesting a chronic neuromodulatory rather than an acute effect on seizures. Similarly, in several experimental models in vivo, it has been reported that there is a lack of stimulation efficacy once an ictal pattern has been already initiated, while closed‐loop application of ictal VNS has no influence on ictal EEG discharges and behavioral seizure manifestations, in contrast to efficacy of pre‐ictal stimulation. In a trial on tachycardia‐triggered vagus nerve stimulation, progression to tonic–clonic seizures was not aborted by ictal VNS, neither was the duration of seizures with objective signs shortened.Acute suppressive effects of direct cortical stimulation on ictal electrographic patterns have been reported for intraoperative stimulation‐evoked seizuresTimely targeted neurostimulation to control severe seizures is of high interest in epilepsy, given that seizures occupy <0.1% of time. Evidence for the ictal effects of neurostimulation is thus of particular interest. We here provide the first evidence that epicranial focal cortex stimulation with high‐frequency pulses can acutely alter brain dynamics in the cortical epileptogenic zone, and terminate sensory seizures prohibiting their otherwise invariable progression to the recruitment of motor regions with severe motor manifestations. The development of closed‐loop approaches for ictal electrical cortex stimulation with a minimally invasive device as used here may thus fill a therapeutic gap for patients with epilepsy. In our experience from the clinical trial recruitment process at our tertiary epilepsy center with a pre‐selected patient population, around 10% of patients could be potential candidates for FCS. In half of these patients, the duration of the focal aware phase of their seizure and the responsiveness of the patients are sufficient to derive a potential benefit from on ictal self‐triggered FCS.33.1The study is registered under DRKS00017833 and CRD42021266440.The study was supported by grant of the German Federal Ministry of Education and Research (13GW0269B) and sponsored by the company PRECISIS GmbH . The study was approved by the local ethics committee.3.2A 44‐year‐old man with a childhood‐onset severe epilepsy highly refractory to multiple antiseizure medications was enrolled in the PIMIDES‐I clinical trial. The patient gave written informed consent for participation in a clinical trial. Key inclusion criteria included neocortical focus localization and accessibility of the epileptic focus for stimulation via an epicranially placed electrode, and the patient's ability to initiate a stimulation bolus during the focal aware phase of seizures.3.3Seizure types, seizure occurrence, and presence or absence of ictal stimulation were documented by the patient in a study‐specific seizure diary.3.4DC‐like stimulation mode (DLS) consisted of 20 ms cathodal pulses at an intensity of 2 mA with an equilibration pulse of 100 ms duration at 0.4 mA in daily 20 minutes sessions for long‐term neuromodulation. Alternating current (AC) high‐frequency (100 Hz) stimulation mode was carried out intermittently by applying short bursts every 2 minutes . Patient‐triggered bolus stimulation was carried out with a 160 μs pulse width, 100 Hz bursts applied for 10‐60 seconds using an external EASEE® Access handheld device. The duration of the stimulation bolus was fixed and the patient had no possibility to change it.All stimulation forms were below perception threshold.MH and ASB contributed to the acquisition and analysis of data. MH, ASB, and VC contributed to the drafting of the text and preparing of figures.ASB has received research support for leading the clinical trial and recruiting patients at the Freiburg Epilepsy Center from the company PRECISIS producing the EASEE device, from the German Ministry of Research and Education, and from the Ministry of Science Baden‐Wuerttemberg for projects to develop intelligent implants for neurostimulation. MH was an investigator in the clinical trials EASEE and PIMIDES and recruited patients at the Freiburg Epilepsy Center.


The aim of this study is to compare the physicochemical properties and yields of pectins extracted from onion waste under hot acid (HAE) and pulsed ultrasound‐assisted extraction (PUAE) methods using different organic–inorganic acids, their mixtures, and pure water. The extraction temperature for experiments carried out under HAE was kept at 90°C for 90 min, whereas PUAE experiments were accomplished at RT in 15 min. In general, HAE gave better pectin yields compared with PUAE due to the significance of the increasing extraction temperature for the release of pectin from the plant matrix. While the maximum pectin yield from onion waste was 16.22% for HAE, the highest yield for PUAE was 9.83%. PUAE provides less time‐ and energy‐consuming extraction of pectin within 15 min and thus seems to be more economic compared with the HAE. According to the physicochemical properties , degree of esterification (DE), methoxyl (MeO), and galacturonic acid  contents) of obtained pectins, extracted pectins were mostly high methoxy pectin. While the DE and MeO values of pectins extracted in organic acid conditions under HAE were higher, these values were found to be higher for pectins extracted in inorganic acids under PUAE. For acid mixtures, the DE and MeO values of pectins under HAE were mostly found to be lower than those under PUAE. Sequential PUAE and HAE methods for the extraction of pectin from onion waste were also found to be useful in terms of obtaining higher yields and better physicochemical properties. The highest pectin yield was 20.32% for the sequential PUAE and HAE methods. FT‐IR analyses of the extracted pectins by both HAE and PUAE methods showed similar vibration bands compared with those of commercial citrus pectin. Pectin extraction under pulsed ultrasound‐assisted and hot‐acid extraction methods in dual acid mixtures from onion waste. Commercial pectin is traditionally obtained from citrus peels, apple pulps, sugar beet pulps, and by‐products of juice. Pectin is widely used in a variety of fields, including gelling agents in jams and jellies, stabilizers, and thickeners in fruit juices, the delivery of bioactive compounds, and biomedical applications such as wound healing and tissue engineering , hydrochloric (HCl), acetic (AA), and sulfuric acids , degree of esterification (DE), methoxyl (MeO), and galacturonic acid  contents of the extracted pectin samples were also determined for all extracted samples. Sequential PUAE and HAE methods for the extraction of pectin from onion waste were also investigated in order to increase the yield and improve the physicochemical properties of pectin. Utilization of sequential methods provided highly enhanced pectin yields and better physicochemical properties.22.12SO4) and HCl acids. Concentrations of acids were 0.1 N. Six gram of dried onion waste powder was poured into 180 mL of extractants for the extraction experiments. The extraction temperature and duration for all experimental conditions were kept at 90°C for 90 min. After completion of the extraction procedure, the solution was filtered to remove residue. Then, pectin was precipitated by the addition of 96% ethanol into the filtrate. The obtained mixture was stored in a refrigerator for 12 h to complete precipitation. The pectin product was then centrifuged and washed four times with ethanol in order to remove contaminants. A NÜVE NF 400 centrifuge (Türkiye) was used during the extraction procedure. Collected pectin in gel form was then dried at room temperature (RT) and stored at 4°C in the refrigerator for further characterization procedures  solid–liquid ratio (SLR). The organic acids used were CA and AA acids, whereas the inorganic acids were sulfuric (H2.22SO4), and different mixtures of these acid solutions were used for the extraction of pectin from onion waste.Extraction of pectin from onion waste was also accomplished using the pulsed ultrasound‐assisted extraction (PUAE) method. PUAE consumes less energy and, therefore, provides power for each bubble and increases their energy storage capacity  was calculated according to the below equation, where P is the weight of the dried pectin and DO is the weight of the dried onion waste.−1. The statistical analysis results were given as the mean standard deviation. The data were analyzed using a single‐factor analysis of variance (ANOVA). The data were tested at a 95% confidence interval for statistical significance.The Gal‐A contents of the extracted pectins were determined by using the spectrophotometric method developed by Blumenkrantz and Asboe‐Hansen . The pot3Pectin extraction steps from dried onion waste are shown in Figure 2SO4 and HCl acids. The extraction temperature and duration for all experimental conditions carried out with the HAE method were kept at 90°C for 90 min, as stated in the previous optimization study  of the obtained pectins indicated that isolated pectins were mostly HMP. Sequential HAE and PUAE methods for the extraction of pectin from onion waste were also found to be very useful in terms of obtaining higher yields and better physicochemical properties. Extracted pectin products by both HAE and PUAE methods were also analyzed by FT‐IR spectroscopy. FT‐IR analyses showed that extracted products showed similar vibration bands compared with those of commercial citrus pectin. Further studies should be focused on altering the purification steps of isolated pectin for better purity and evaluating extracted pectin products for different industrial purposes, including biofuel and bioenergy.Emine Şen: Formal analysis ; investigation ; validation ; visualization . Ersen Göktürk: Writing – original draft (lead); writing – review and editing (lead). Vugar Hajiyev: Investigation ; validation . Erdal Uğuzdoğan: Conceptualization (lead); methodology (lead); resources (lead); validation ; writing – original draft ; writing – review and editing .The authors have no competing interests to declare that are relevant to the content of this article.This article does not contain any studies with human participants or animals performed by any of the authors.Data S1Click here for additional data file.