This paper integrates trait, reasoned action, and habit approaches to develop and test a mechanistic account of valuation, prioritization, habituation, translation, and inhibition routes.We tested five potential pathways from self-control to behavior, termed the N = 663 adults) completed survey measures of reasoned action approach variables and habits in relation to eight health behaviors and the Brief Self-Control Scale. Three months later, participants reported their behavior. Multi-level modeling was used to test pathways across behaviors.At baseline, participants  or avoidance responses  were at issue.The present research offers new insights into why self-control promotes health behavior performance, and how deficits in self-control might be offset in future behavior-change interventions. Individuals high in self-control do more health behaviors partly because they are better at following through on their intentions. Self-control was associated with both increases in desired or approach behaviors and with decreases in undesired or avoidance behaviors . The average correlation between self-control and dietary and weight outcomes was r+ = .17 across 14 studies ).cognitive and affective attitudes, respectively; ) The present research aims to offer a mechanistic account of the relationship between self-control and health-related intentions and behavior using RAA and habit constructs. According to Berkman et al. , “[t]herWhereas the valuation route suggests that high self-control leads to stronger beliefs about the enjoyment or instrumental benefits of health behaviors, increased perceptions of normative support, and greater perceived ease of acting healthy, the prioritization pathway concerns how self-control influences the weight attached to these different considerations during intention formation. The valuation pathway is a mediation model (self-control → cognitions → intentions → behavior) whereas the prioritization pathway is a moderation model involving the hypothesis that higher self-control leads to improved prediction of intention by cognitive attitudes, perceived behavioral control, and injunctive norm and weaker relationships between intentions and affective attitudes, descriptive norms, and habits.resist descriptive norms but it is needed to comply with injunctive norms. In sum, the prioritization pathway predicts that as self-control increases, cognitive attitudes, perceived behavioral control, and injunctive norms hold greater sway over intentions whereas affective attitudes, habits, and descriptive norms become less influential.Self-control is associated with prioritizing long-term over short-term goals  and witLike the valuation pathway, the habituation pathway involves a mediation model but habits form the mediator here rather than attitudes, norms, or perceived behavioral control. The idea is that people with high self-control do not have to solely rely on effortful control of impulses to promote behavior change; they have also developed habits that can efficiently and effectively facilitate behavioral goals. Adriaanse et al.  offered The translation pathway concerns the hypothesis that self-control moderates the relationship between intentions and behavior such that higher self-control leads to improved translation of intentions into action. At least two mechanisms could underlie this pathway. First, self-control could be associated with more stable intentions, and research indicates that intention stability moderates intention-behavior consistency e.g., , 42). Se. Se42]).The final, inhibition pathway involves the traditional conceptualization of self-control. As Fujita , p. 355)553], incsimultaneous test of the five pathways. To offer a comprehensive test of these pathways, we examined eight different health behaviors among a large sample over a 3-month period and used multilevel modeling to test associations across behaviors. We examined both approach behaviors  and avoidance behaviors  and tested whether approach vs. avoidance behavior moderated each of the five pathways  analysis of the role of autonomous motivation in self-control effects with the 5-pathway model and test whether this variable contributes to the valuation pathway. Relatedly, it will be important for future research to discover whether self-control promotes intention realization by generating stable or well-formed intentions  or by facilitating the formation of implementation intentions . It was Although a longitudinal design permits strong inferences, the fact that we had only two timepoints, 3 months apart, meant that moment-by-moment changes in situational affordances and strategy use could not be captured. Ecological momentary assessment (EMA) methods  could r > .5), while habit, affective attitudes and perceived behavioral control had medium-large sized effects (.3 < r < .5), and self-control and other variables had small-medium sized effects (.1 < r < .3).There are empirical limitations too. First, behavior was measured using self-reports. It was not feasible to obtain objective measures of the multiple behaviors examined here, and so replication of the present findings using non-reactive outcomes should be a priority for future research. Second, descriptive and injunctive norms were measured using single items and multi-item tests would be valuable to corroborate our findings. Third, we used single-item measures of one particular formulation (performance frequency × context stability) of habits. Future tests should also consider multi-item measures of habit and indices of perceived automaticity (see , for a rNotwithstanding these limitations, the present research breaks new ground and has implications for future research. The analyses presented here constitute one of the first attempts to integrate trait, reasoned action, and habit approaches. Although the findings were largely consistent with Ajzen’s  proposalkaac053_suppl_Supplementary_FiguresClick here for additional data file.


Stroke is an emergency in which delays in treatment can lead to significant loss of neurological function and be fatal. Technologies that increase the speed and accuracy of stroke diagnosis or assist in post-stroke rehabilitation can improve patient outcomes. No resource exists that comprehensively assesses artificial intelligence/machine learning (AI/ML)-enabled technologies indicated for the management of ischemic and hemorrhagic stroke. We queried a United States Food and Drug Administration (FDA) database, along with PubMed and private company websites, to identify the recent literature assessing the clinical performance of FDA-approved AI/ML-enabled technologies. The FDA has approved 22 AI/ML-enabled technologies that triage brain imaging for more immediate diagnosis or promote post-stroke neurological/functional recovery. Technologies that assist with diagnosis predominantly use convolutional neural networks to identify abnormal brain images . These technologies perform comparably to neuroradiologists, improve clinical workflows , and improve patient outcomes . Two devices are indicated for post-stroke rehabilitation by leveraging neuromodulation techniques. Multiple FDA-approved technologies exist that can help clinicians better diagnose and manage stroke. This review summarizes the most up-to-date literature regarding the functionality, performance, and utility of these technologies so clinicians can make informed decisions when using them in practice. Stroke is a neurological emergency and the fifth leading cause of death in the United States ,2,3. EstTools to improve the speed and accuracy of stroke diagnosis and treatment could improve patient outcomes. Artificial intelligence/machine learning (AI/ML) will play a large role in developing such tools. AI/ML in healthcare is growing at 40% per year, and its adoption has the potential to cut USD 150 billion in healthcare costs by 2026 , analyziWe sought to identify all FDA-approved, AI/ML-enabled medical technologies with indications for ischemic stroke and/or ICH. To compile this list, our search had two components.First, we examined the previously cited  databaseSecond, we conducted an internet search in accordance with previously described methods  to identCombining the results from both search components, we assessed 28 ischemic stroke-/ICH-related technologies. After excluding 6 duplicates, we arrived at a total of 22 unique technologies .We queried PubMed and relevant company websites to assess the most up-to-date (post-2018), technology-related literature published in peer-reviewed journals. The PubMed search was conducted by querying the database with the device name , and company websites were searched for “research” or “data” pages that cited studies involving the company’s technology. Studies published before 2018 were excluded, and we did not include review articles, editorials, or letters to the editor. Original, primary research that directly assessed the clinical performance of an AI-enabled technology for stroke diagnosis or management in humans was included. For each publication, we collected data regarding metrics commonly used to assess ML algorithm performance, such as accuracy, specificity, sensitivity, positive predictive value, negative predictive value, and area under the receiver-operator curve (AUC). We report results from 45 publications. This study was IRB-exempt.Our search revealed 22 FDA-approved, AI/ML-enabled technologies indicated for stroke diagnosis and management. A total of 18 companies developed these 22 technologies, with a majority  headquartered outside of the United States. The first approval was in February 2018. All initial approvals were for technologies that assist with ischemic stroke diagnosis, but two out of the last three approvals (BrainQ and IpsiHand) were for devices indicated for post-stroke rehabilitation . Here, wAn important application of AI/ML is the automated detection of large vessel occlusions. Viz ContaCT, commercially known as Viz LVO, was the first FDA-approved AI/ML-enabled technology indicated for stroke and uses a convolutional neural network (CNN) as the underlying algorithm to detect LVOs from CT angiography (CTA). In data submitted to the FDA, Viz LVO displayed an area under the receiver operating curve (AUC) of 0.91 and reduced time from scan reading to specialist notification from 58 to 7 min , indicatRapidAI is a technology platform similar to Viz.ai. In addition to LVO identification on CTA , RapidAI includes software to analyze CT perfusion (RAPID-CTP) and MRI (RAPID-MRI) images for stroke triaging . Though Newer technologies for LVO identification include CINA-LVO  and HALOAssessing the extent of irreversible ischemic damage to guide treatment decisions is equally important as identifying suspected LVOs. The Alberta Stroke Program Early CT Score (ASPECTS) is one widely used method for accomplishing this task. While diffusion-weighted MR imaging provides the most accurate information regarding acute infarction, CTH is more readily available in the acute setting. FDA-approved Rapid ASPECTS determines ASPECTS from CTs in patients with known MCA or ICA occlusions, but not for primary interpretation of CT images. In addition, the technology is only intended for use on GE Lightspeed VCT Scanners . OverallAnother class of FDA-approved, AI/ML-enabled technologies for the management of stroke includes technologies that analyze CTP or MR perfusion images to assess the core and penumbra volumes and predict final infarct volumes. CTP can demonstrate ischemic tissue, which consists of non-salvageable tissue and at-risk tissue that could be rescued with successful reperfusion. CTP analysis provides specific parameters, including cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT). Rapid-CTP is a comprehensively studied tool for CTP analysis within the broader RAPID platform and performs well in estimating final infarct volumes, with high accuracy and relatively strong correlations to the gold standard  ,43,44,45Technologies indicated for the detection of ICH generally performed better than those indicated for LVO detection . BriefCaCINA-ICH has similar reported performance in ICH detection compared to BriefCase C. NPVs rRapid-ICH , with PPTools for post-stroke rehabilitation require further development, especially given the poor natural recovery that is often seen with stroke . There iAn Israeli-based company, BrainQ, is developing a non-invasive brain-computer interface (BCI) device that leverages extremely low frequency and low intensity electromagnetic fields (ELF-EMF) to promote post-stroke recovery ,83. AfteBrainQ received FDA breakthrough status in February 2021 based on results from a pilot trial of 25 patients with a history of sub-acute ischemic stroke. Patients who received 40 min of ELF-EMF treatment 5 days a week for 8 weeks had superior recovery compared to the sham group as assessed by multiple metrics  and did not report any adverse events . BrainQ IpsiHand Upper Extremity Rehabilitation System (IpsiHand), granted breakthrough status by the FDA in April 2021, is the first FDA-approved device to use BCI technology to facilitate motor rehabilitation in patients who are more than 6 months post-stroke. The device uses an EEG electrode headset to translate neural activity of movement intent from the uninjured brain hemisphere into physical movements of a robotic exoskeleton worn around the impaired hand, wrist, and forearm . A studyIn total, the FDA has approved 22 unique AI/ML-enabled technologies to assist clinicians with the diagnosis or management of stroke or ICH. The 20 technologies indicated for assistance with diagnosis can save valuable time by triaging potentially troubling scans and reducing the need for labor-intensive and time-consuming tasks such as segmentation. These technologies can ultimately reduce delays for patients to receive life-saving interventions. Adoption of these technologies has been strong, with RAPID in use at 1800 and Viz.ai in 900 hospitals ,95. In aGiven the proprietary nature of the technologies discussed here, specific details about ML model design and algorithms are not publicly available. However, most models that underlie technologies indicated for stroke diagnosis leverage deep learning in the form of convolutional neural networks. The reasons for performance variation across these technologies are multifactorial and likely due to a combination of model design and quality/quantity of testing data. Model design in ML development involves determining model structure  and hyperparameters  and still relies on trial and error ,99,100. There is great promise for AI/ML-enabled technologies in stroke diagnosis and management. The automated process can minimize intra-/inter-rater variability and provide support for less experienced or non-specialized physicians. As such, integration of these software solutions into patient care can improve the speed and accuracy of diagnosis. However, there are still issues to be addressed. The first is improving algorithm performance. Though many studies have shown that these AI/ML algorithms can perform comparably to or even outperform neuroradiologists, the technologies can fall short in certain instances. The anatomical location of the disease or patient-to-patient anatomical variation is a common cause of impaired algorithm performance. Difficulties with LVO identification were seen with anatomical variations such as early unilateral MCA or petrous ICA . AdditioThe second issue to address with the use of these technologies involves the use of black-box AI/ML algorithms. Neural networks, and “deep” neural networks in particular, can tend to be “black box” algorithms in that they arrive at conclusions and outputs without readily providing information regarding their analytical process. As neural networks tend to underlie many AI/ML-enabled tools in healthcare today, some have argued that these black-box algorithms must have increased transparency before being used in high-stakes healthcare settings. There have been efforts to make AI/ML algorithms more interpretable to the end user ,103, witThe last issue that must be addressed involves reimbursement for hospitals that utilize these technologies. In 2018, the Centers for Medicare and Medicaid Services (CMS) approved payment for use of Viz LVO through a “New Technology Add-on Payment”, marking the first time CMS reimbursed AI/ML-enabled software through this mechanism . RapidAIOverall, the studies analyzed here show that AI/ML-enabled technologies for stroke diagnosis are performing equally to or even exceeding human performance on certain metrics. Generally, these technologies have higher sensitivities and NPVs compared to specificities and PPVs, further highlighting their role in triaging and assisting clinicians rather than making definitive clinical decisions. In the coming years, as these technologies are exposed to more cases and increased clinical data, their performance should only improve, but as stated above, there is still a need for larger, multi-center trials to continue monitoring and comparing technology performance. There is a common theme in the studies assessed here: the use of these technologies can improve clinical workflows. However, few studies further correlated increased efficiency with quantifiable improvements in patient outcomes. Some studies report improvements in, for example, the NIH stroke scale, but there is still perhaps a need for long-term follow-up to assess if the workflow efficiency facilitated by these technologies truly translates to better long-term clinical outcomes. Similarly, there are inconsistencies across studies regarding the timing of imaging analysis, as only a few assessed the differential impact of using AI/ML-enabled technologies in the acute  versus the sub-acute  timeframes. This is particularly important when analyzing zones of ischemia and the viability of tissue post-stroke. In the same vein, there must be more consistency in reporting the time technologies take to evaluate imaging. As the complexity of medical imaging increases, the algorithms underlying these technologies must be refined to efficiently process scans at a speed that is at least equivalent to, if not faster than, human performance.To facilitate the approval and clinical utilization of emerging AI/ML-enabled technologies, the FDA has created protocols to better assist researchers in developing these technologies and navigating the FDA approval process . These pOur study has a few limitations. First, though the majority of papers analyzed here were identified in PubMed, some papers were only discovered after searching company websites. This may have introduced selection bias to our literature search, though the minority of papers were found by searching company websites. Second, our study focuses on FDA-approved solutions, but there are many emerging technologies in the research pipeline that are not discussed here. Third, given the proprietary nature of the technologies described here, we are unable to specifically comment on the strengths and weaknesses of the design of the algorithms that underlie these technologies.FDA-approved AI/ML-enabled technologies for stroke diagnosis and management have proven to be powerful tools in improving the efficiency and accuracy of patient care decisions by physicians. Many of these technologies use convolutional neural networks as their underlying algorithm and have approached or even exceeded the gold standard of human performance when tested using real-world data. Future work is needed to further refine the performance of these technologies in, for example, patients with aberrant anatomy and to compare technologies in a head-to-head manner with large, multi-center studies.


Cerebral amyloid angiopathy (CAA) is a common disease and the most common cause of lobar hemorrhages in the elderly. Usually, deep-seated microhemorrhages preclude the diagnosis of CAA. In this study, we sought to estimate the frequency of deep-seated microbleeds on MRI in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy. In addition, we describe a cohort of patients with cortical and deep-seated microbleeds on MRI and a histopathological specimen available from lobar hematoma evacuation.Retrospective database search for histopathological specimens from lobar hematoma evacuation and review of imaging findings (CT and MRI) and patient charts was performed.n = 4, other diagnosis n = 8, no MRI n = 43, and no BOLD-based sequence n = 1). Of the remaining 32 patients, 25 patients (78%) did not harbor deep-seated lesions on MRI, of which 17 patients had histopathological features of CAA. A total of seven patients harbored deep-seated CMB. Of these seven patients, three  had histopathological features of CAA.Between 1 January 2012 and 31 December 2020, 88 specimens from 88 patients were available. A total of 56 specimens were excluded (no brain tissue in the specimen Approximately 15% of patients with histopathologically diagnosed CAA harbor deep-seated microbleeds. This finding may add to the discussion on how to identify patients with CAA and deep-seated CMB. Cerebral amyloid angiopathy (CAA) is a common disease in the elderly population and the most common cause of lobar hemorrhages in elderly patients . Its diaStrictly deep-seated hemorrhagic lesions are the hallmark of hypertensive arteriopathy (HTN-A). Patients displaying features of CAA and harboring deep-seated CMBs, i.e., mixed location hemorrhages/microbleeds (MLH) , are mosIn this study, we sought to estimate the presence of deep-seated CMBs in patients with lobar hemorrhages and histopathology evidence for cerebral amyloid angiopathy.We retrospectively included patients from our radiological, clinical, and histopathological database with the following inclusion criteria: (1) available brain specimen from lobar hematoma evacuation demonstrating either cerebral amyloid angiopathy or no apparent vessel pathology  and (2) available MRI including a BOLD-based sequence within 3 months of the biopsy. Patients with signs of CAA-related inflammation (CAA-ri) were excluded.Hematoma evacuation was performed according to the judgment of the attending neurosurgeon. The obtained brain tissue was processed using standard procedures. The specimens were fixed in formalin and embedded in paraffin stained with hematoxylin and eosin as well as Congo red. If the typical yellow-green birefringence was found using polarization microscopy, additional immunostaining against amyloid β was performed to allow for amyloid subclassification by a board-certified surgical pathologist with a special interest in amyloidosis (CR). Any presence of staining for amyloid β was rated as CAA , 10 Fig, i.e., mThe MLH group was defined by the presence of one or more deep-seated CMB in the brain stem, thalami, or basal ganglia  anatomical template)  in whichAll MRI scans  were reviewed by a board-certified radiologist (UJK) and a board-certified neurologist (NGM) blinded to history, clinical diagnosis, and laboratory parameters using all available imaging materials in consensus. The presence of the following imaging findings is reported following the STRIVE criteria (if applicable) : acute ahttps://www.ed.ac.uk/clinical-sciences/edinburgh-imaging/education-teaching/short-courses/training-tools/edinburgh-criteria-for-caa-associated-ich-training. FLP was defined as a hemorrhagic intraparenchymal extension from the main hemorrhage which is longer than its width at the exit point from the main hemorrhage (The CT scans of the acute stage were reviewed by two board-certified neuroradiologists (AN and HS) in consensus regarding the presence of finger-like projections FLP) and subarachnoid hemorrhage (SAH) adjacent to the acute lobar hemorrhage after completion of the online training using the Edinburgh Criteria  for CAA-morrhage , F.LP and suThe size and location of hemorrhages were measured by one board-certified neuroradiologist (MH) using the ABC/2 or ABC/3 rule for round and irregular hemorrhages, respectively .Demographic and clinical information was extracted from the patient's chart, namely age, sex, history of arterial hypertension, diabetes mellitus, dyslipidemia, antithrombotic drugs and/or statin intake, elevated creatinine, elevated low-density lipoprotein (LDL), and early (within 6 months) ICH-related death.t-test, Wilcoxon–Mann–Whitney U-test, chi-square test, or Fisher's exact test as appropriate. The agreement between the two raters for SAH and FLP was calculated using Cohen's κ. A p-value of < 0.05 was considered to be statistically significant. R  was used for all calculations.Variables are displayed using the mean and standard deviation or median and interquartile ranges (IQR) as appropriate. Comparisons were made with a two-sided The ethics committee of the medical faculty of the University of Kiel approved this retrospective study (B 255/18).n = 3, hemorrhagic tumor n = 1, and vascular malformation n = 4) was made. In four specimens, no blood vessels were present and were excluded. In 43 patients, no MRI was available. In one patient, an MRI but no BOLD-based sequence was available. Of these patients without MRI, 25 (57%) were diagnosed with CAA. Of the remaining 32 specimens of 32 patients, all patients had an MRI within 3 months of the hematoma evacuation. All MRI scans were performed at 1.5 T including susceptibility-weighted images. A total of 25 patients did not display any deep-seated CMB. Of these 25 patients, 17 were finally diagnosed with CAA . Severity grading was “severe” in all three cases. In four patients, no signs of CAA or any other blood vessel pathology were present. Apart from the presence of deep-seated CMB, all seven patients also had cortical CMBs. Of the seven hemorrhages, five were right-sided: three were parietal, three were frontal, and one was temporal. Typical MRI and CT imaging markers of CAA such as enlarged perivascular spaces, cortical superficial siderosis, and finger-like projections were found both in CAA and non-CAA patients . FurtherCohen's κ for SAH was 1 (perfect agreement) and 0.72 for FLP .In our cohort, 15% of the patients histopathologically diagnosed with CAA according to the Boston criteria 2.0 harbored deep-seated CMB on MRI. However, deep-seated CMB precluded the diagnosis of CAA. If a histological specimen is present, this caveat does not apply, but in clinical practice, a cortical biopsy is only rarely performed. Even in patients with lobar hemorrhages, neurosurgical evacuation is not always warranted.The prevalence of deep-seated CMB in CAA of 15% in our cohort matches the observation that ~15% of patients with MLH have cSS , 5. OtheCAA is the consequence of amyloid accumulation in cerebral vessels which renders them fragile and prone to rupture, hence the multitude of possible hemorrhagic manifestations  . For unkEspecially in older patients, it is not uncommon and biologically not excluded for CAA and HTN-A to coexist . A high The sensitivity of the original Boston criteria could be increased from 44%  to 95% wWeaknesses of our study include all the shortcomings associated with the retrospective nature of this study and its limited sample size. As routine medical treatment and diagnostics as per local protocol were performed, a large share of patients had no MRI available which allowed an in-depth analysis with larger case numbers. Furthermore, systematic biopsy or hematoma evacuation was not performed in all patients presenting with lobar hematoma as it was deemed clinically not warranted or not warranted by the local protocol. Moreover, in cases with clear clinical and MRI presentation and even more so in cases with “possible CAA,” a biopsy is rarely performed. In summary, the true prevalence cannot reliably be deducted from the data presented here which can only be regarded as a rough approximation. Although Boston criteria 2.0 do not require immunostaining, it is regarded as the most sensitive technique to detect amyloid deposition. As per the local protocol, routine staining including Congo red and polarization microscopy was performed in all cases. Amyloid-positive cases may have escaped detection but the exact sensitivity of immunostaining in comparison with conventional staining is unknown.Deep-seated CMBs are estimated to be present in ~ 15% of patients with CAA. This finding may add to the discussion on how to identify patients with CAA and deep-seated CMB. Future studies should assess the gain and trade-offs in sensitivity and specificity by not excluding patients with deep-seated CMBs.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee of the Medical Faculty of the University of Kiel. The ethics committee waived the requirement of written informed consent for participation. The participants consented to retrospective analysis of the data collected during routine work-up during the hospital stay. In case the permission could not be retrieved, only anonymized data were used.NGM and UJ-K: conception and design. UJ-K, NGM, CR, HS, and AN: formal analysis. UJ-K: wrote the first version of the manuscript. All authors: data acquisition, edited, and approved the manuscript.


Acute respiratory distress syndrome (ARDS) is characterized by non-cardiogenic pulmonary edema caused by inflammation, which can lead to serious respiratory complications. Due to the high mortality of ARDS caused by sepsis, biological markers that enable early diagnosis are urgently needed for clinical treatment.In the present study, we used the public microarray data of whole blood from patients with sepsis-induced ARDS, patients with sepsis-alone and healthy controls to perform an integrated analysis based on differential expressed genes (DEGs) and co-expression network to identify the key genes and pathways related to the development of sepsis into ARDS that may be key targets for diagnosis and treatment.Compared with controls, we identified 180 DEGs in the sepsis-alone group and 152 DEGs in the sepsis-induced ARDS group. About 70% of these genes were unique to the two groups. Functional analysis of DEGs showed that neutrophil-mediated inflammation and mitochondrial dysfunction are the main features of ARDS induced by sepsis. Gene network analysis identified key modules and screened out key regulatory genes related to ARDS. The key genes and their upstream regulators comprised a gene panel, including EOMES, LTF, CSF1R, HLA-DRA, IRF8 and MPEG1. Compared with the healthy controls, the panel had an area under the curve (AUC) of 0.900 and 0.914 for sepsis-alone group and sepsis-induced ARDS group, respectively. The AUC was 0.746 between the sepsis-alone group and sepsis-induced ARDS group. Moreover, the panel of another independent blood transcriptional expression profile dataset showed the AUC was 0.769 in diagnosing sepsis-alone group and sepsis-induced ARDS group.Taken together, our method contributes to the diagnosis of sepsis and sepsis-induced ARDS. The biological pathway involved in this gene biomarker panel may also be a critical target in combating ARDS caused by sepsis.The online version contains supplementary material available at 10.1186/s12920-023-01595-8. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid and widespread inflammation of lungs, accompanied by hypoxemia, reduced lung compliance, and chest imaging examination showing bilateral alveolar opacity . GloballSepsis is the most common trigger of ARDS and the highest cause of ARDS mortality . ClinicaHigh throughput gene analysis was a powerful tool to reveal the key pathways and genes of diseases. In recent years, it has also been applied to the research of ARDS. A Genome-wide association studies pointed out several candidate genes were related to the development of ARDS, including the interleukin 6 (IL6), interleukin 10 (IL10), interleukin 1 receptor antagonist (IL1RN), vascular endothelial growth factor A , angiotensin-converting enzyme (ACE), soluble mannose-binding lectin 2 (MBL2) and visfatin (NAMPT) . Acosta-Recently, with the development of analytical techniques in systems biology, gene network analysis has been widely used in disease-related high-throughput omics studies . Gene neIn this study, we conducted an integrated analysis on expression level and network level of the whole blood microarray profiles of pneumonia-induced sepsis patients, sepsis-induced ARDS patients and healthy controls Fig. . The nethttps://www.ncbi.nlm.nih.gov/geo/) is a free global public database storing genomics and transcriptomics data, including high-throughput sequencing and microarray expression files. We searched the GEO database for ARDS-related studies and found two datasets that met our requirements, including samples of healthy controls, pneumonia-induced sepsis alone, and ARDS developed from pneumonia-induced sepsis. The larger sample size dataset (GSE32707) was used as the discovery set, and another dataset (GSE66890) was used as the validation set. Institutional Review Board approval was not required, because our study was based on a public database and did not involve in animal or human samples.The Gene Expression Omnibus (GEO) database  . Outlierp-value less than 0.05 was used as the threshold of significance.In the present study, we used limma package of R to identify differential expressed genes (DEGs) between sepsis-alone group, sepsis-induced ARDS group and healthy control group . Benjamihttp://www.ingenuity.com). These two approaches represent two different philosophies on the alteration of gene function. GSEA allows the use of all genes to investigate the alterations of biological functions caused by disease, enabling us to observe which biological functions tend to be up-regulated and which to be down-regulated [p-values were calculated to filter significance (p < 0.05).Gene Ontology (GO) annotation and enrichment analyses were performed using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis software , a web-based database was used to construct the protein-protein interaction network for genes of key modules. The Cytoscape software  was employed for visualizing the PPI network. The CytoHubba plugin (ver 0.1) provided degrees of each node in the PPI network and the top 10 genes were considered as hub genes [STRING  and LTF  showed a trend of expression differences among groups , and can well diagnose ARDS developed by sepsis (AUCARDS−Sepsis=0.746). An independent dataset confirmed (GSE66890) the united gene panel had a potential diagnosis efficiency, with an AUC of 0.769  and IPA analysis  suggested that neutrophil-mediated inflammatory response and mitochondrial dysfunction are the major characteristics of ARDS caused by sepsis. As we all know, ARDS was an acute inflammatory disease , 32, andFurthermore, co-expression network analysis and PPI network helped us identified four hub DEGs were identified. Among these hub genes, colony stimulating factor 1 receptor (CSF1R), a cytokine which controls the production, differentiation, and function of macrophages, was significantly up-regulated in sepsis-alone group and sepsis-induced ARDS group. Previous evidence showed excessive recruitment and activation of macrophages from the blood, as well as resident alveolar macrophages (AM), may be key factors in the development of ARDS –46. MacrMoreover, we also identified two possible upstream URFs of the hub genes, which were significant increased in sepsis patients and ARDS patients Fig. . LactotrIn current study, we performed an integrated analysis based on gene expression and gene network and identified key regulators in the development of sepsis to ARDS. A six-gene panel including EOMES, LTF, CSF1R, HLA-DRA, IRF8 and MPEG1 was discovered and validated with a high accuracy both in sepsis subjects and sepsis-induced ARDS subjects. Our findings provide meaningful biomarkers for the diagnosis, and clues for the pathogenic mechanism of sepsis and ARDS.There were also some limitations in this study. Firstly, this study was limited by the search results of public databases and sample sizes. Secondly, our study was based on bioinformatics methods and screened out the marker genes of sepsis-induced ARDS with high diagnostic efficiency. The diagnostic results of these genes need to be verified in a larger datasets. Thirdly, the lack of in vivo and in vitro proof. For our next work, we will collect a large-scaled clinical samples from multi centers to confirm the stability of the predictive power of these markers, and confirm their therapeutic potential through in vivo and in vitro experiments.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4Supplementary Material 5


Estimates of local intercepts derived from GWPR exhibited differences in HIV/AIDS self-testing uptake. Overall, the output of this study displays interesting findings on the levels of spatial heterogeneity of factors associated with HIV/AIDS self-testing uptake across South Africa, which calls for district-specific policies to increase awareness of the need for HIV/AIDS self-testing.Increased HIV/AIDS testing is of paramount importance in controlling the HIV/AIDS pandemic and subsequently saving lives. Despite progress in HIV/AIDS testing programmes, most people are still reluctant to test and thus are still unaware of their status. Understanding the factors associated with uptake levels of HIV/AIDS self-testing requires knowledge of people’s perceptions and attitudes, thus informing evidence-based decision making. Using the South African National HIV Prevalence, HIV Incidence, Behaviour and Communication Survey of 2017 (SABSSM V), this study assessed the efficacy of Generalised Linear Poisson Regression (GLPR) and Geographically Weighted Poisson Regression (GWPR) in modelling the spatial dependence and non-stationary relationships of HIV/AIDS self-testing uptake and covariates. The models were calibrated at the district level across South Africa. Results showed a slightly better performance of GWPR (pseudo R Sub-Saharan Africa accounts for 70% of Human Immunodeficiency Virus/Acquired Immunity Deficiency Syndrome (HIV/AIDS) infections around the globe . This isFindings from the 2017 SABSSM survey also highlighted a higher prevalence of HIV/AIDS, and this was noted to have been perpetuated by social inequalities in South Africa, with most blacks living in poverty . Similarp = 0.001), the study reported that HIV/AIDS positive respondents on ART were less likely to have numerous sexual partners, thus adopting condom use in sexual encounters compared to HIV/AIDS respondents who were not on ART. HIV/AIDS-infected adults on ART often shifted their sexual behaviours in response to their HIV/AIDS-positive status. Analysing relationships between HIV/AIDS and socioeconomic issues between 2011 and 2016 in Sub-Saharan African countries, Sun et al. [Extant literature investigated the variation in HIV/AIDS prevalence based on human perception, behaviour patterns, attitudes, norms, and stereotypes e.g., ,11,12,13Allocation of resources for HIV/AIDS testing to areas of greatest need is key to controlling the epidemic. Most importantly, it is worth noting that people with HIV infection are generally asymptomatic for several years before the virus progresses to AIDS . The intVarious studies have explored the association of HIV testing uptake with spatial patterns, socioeconomic status, and demographics, etc., ,21,22,23It is therefore important to find factors that influence HIV/AIDS self-testing uptake and analyse the interaction between them, by taking into account unaddressed location variables, thus determining districts that require closer attention. Notably, this is the foundation for constructing a spatial dynamics model, as well as the basis for developing location and evidence-based intervention strategies. Although evidence from the literature, ,25 proviThe study utilised the 2017 SABSSM V data  which waThe global spatial autocorrelation  was computed to assess whether the district level spatial distribution of HIV/AIDS self-testing uptake and the covariates was dispersed, clustered, or random. Moran’s I , was utik-th explanatory variable, i-th model parameter, index i refers to the district, and i-th random error term.When predicting discrete, non-negative, and non-continuous variables , it is more appropriate to use Generalised Linear Models (GLM) to determine the relationship between outcome and explanatory variables . HoweverYi is the observed count data at district locations i. EYi)( is the HIV/AIDS self-testing uptake at district locations i. β0(s), β1(s), β2(s), …, kβ(s) are the spatially varying coefficients, which may differ across different districts. xi1, xi2, …, kix are the predictor variables at district locations i. ln is the natural logarithm. In this study, spatially varying coefficients are estimated using bi-square, kernel function that assigns weights to nearby observations. Thus, observations further from a particular district location have less influence on the estimation of the coefficients.GLPR is not capable of capturing spatial dependence in data, and it ignores the spatial correlation in the estimation of relationships ,44. Equa2 (Equation (3)), the Akaike information criterion (AICc) (Equation (4)) and deviance residuals.The diagnosis of the GLRP model was established by analysing the pseudo RAIC (Equation (4)) that estimates the distance between a model and an ideal but unobservable model [L and allows visualisation of spatial difference of the explanatory power of the model. Higher percent deviance values are more desirable. Furthermore, all analysis and maps for this study were computed and generated in ArcGIS Pro 3.0.2 .Overall model performance between GLPR and GWPR was established using local percent deviance explained. Percent deviance explained is comparable to the local determination coefficient  in the relationships between HIV/AIDS self-testing uptake with covariates used in the study  from GLPR. Furthermore, as indicated from the output of the analysis of deviance residuals derived from GWPR using Moran’s I statistics , the output illustrated a lack of spatial autocorrelation indicating spatial randomness  in Sedibeng, Gert Sibande, Uthukela, eThekwini, iLembe, and King Cetshwayo districts. On the contrary, Central Karoo and Namakwa districts recorded the lowest count of HIV/AIDS self-testing uptake ranging between 37 and 80. Model performance in terms of pseudo R2 = 0.91 .Statistically significant district level clustering of deviance residual confirms spatial dependency of HIV/AIDS self-testing uptake prevalence using a global model. High negative clustering  was predominantly observed in the districts around Northern Cape, Western Cape, and Eastern Cape including Namakwa, West Coast, Garden Route, and Sarah Baartman districts. Contrary, high positive clustering  was observed in Capricorn Bojanala, City of Tshwane, City of Johannesburg, and Nkangala districts, etc. Theoretically, if the output of the spatial autocorrelation analysis exhibits a lack of spatial dependence, then the GLRP model is sufficient to explain the relationship between HIV/AIDS self-testing and covariates. However, from the output derived from the models, the spatial distribution of deviance residuals  showed eGWPR was computed to analyse the influence of covariates on modelling HIV/AIDS self-testing uptake and the result showed a slight improvement in local model performance compared to the global model . FurtherThe local percent deviance explained shows spatial variation in the explanatory power of the GWPR model across different districts in South Africa in terms of predicting the relationship between HIV/AIDS self-testing uptake and the covariates . A signiGWPR coefficients  present This study explored the effectiveness of GLPR and GWPR models in examining the spatial dependence and non-stationary relationships of HIV/AIDS self-testing uptake and the covariates. Output from the study shows that 12% of the relationship between HIV/AIDS self-testing uptake and the covariates used in the study cannot be captured by the global model, compared to 9% by the local model. The results show the inefficiency of the global model due to the non-consideration of the scale of geographical processes associated with HIV/AIDS self-testing uptake. Local regression models capture local spatial disparities in the relationships between outcome and explanatory variables . This isHIV/AIDS self-testing has been recognised in the literature as having significant advantage of increased privacy and confidentiality, as well as convenience compared to conventional HIV/AIDS testing administered by health professionals ,30,52,53Local percent deviance differed across districts illustrating the difference in the combined statistical impact of the local model variables and this could be attributed to unique demographic characteristics. Similar observations were reported by Jooste et al.  who mappWith notable variance in the strength of GWPR coefficients, the study identified districts with both significant positive and negative relationships between each explanatory variable and HIV/AIDS self-testing uptake. The positive association between more than 6 months since the last healthcare profession visit and HIV/AIDS self-testing highlighted in districts around Northern Cape  Eastern Cape , and Western Cape  could be highlighting good health amongst respondents, hence less frequent visits to medical professionals. Further explanation of the positive association between HIV/AIDS self-testing and fewer healthcare professional visits could be associated with lifestyle and access to healthy food items thus boosting their immune system. This is more apparent in urban districts (City of Cape Town and Nelson Mandela Bay), where access to nutritious retail food items is better compared to the rural districts . On the Perceptions of excellent health status can convince people to have a negative attitude towards acceptance of HIV/AIDS self-testing. Excellent health status is regarded as an essential indicator of satisfaction with life in relation to any illnesses one can succumb to. This subjective perception of an individual’s sense of excellent well-being, with the absence of feelings of discomfort or pain and psychological consequences of having a health problem, contributes to hesitance in HIV/AIDS self-testing initiatives . NegativSome of the limitations of this current study include the following. The cross-sectional design of the survey limits the causal inferences between HIV/AIDS self-testing uptake with the analysed covariates. Thus, there may be a high degree of municipal district heterogeneity. The findings of this study should only be explained at the county-scale level and local inferences can be misleading/inaccurate due to ecological fallacy.This study demonstrated the efficacy of GWPR in modelling HIV/AIDS self-testing uptake and its associated covariates. It has been noted that HIV/AIDS self-testing uptake provides a chance for individual testing to be performed inconspicuously, at one’s convenience. GWPR analysis enables the identification of the specific predictors at each local and specific district municipality. Modelling the uptake of HIV/AIDS self-testing enables targeted interventions on reluctant individuals, by developing evidence-based and location intelligence interventions for areas in most need. The contributing factors analysed in this study, i.e., excellent health, more than 6 months since last health professional visit, and at least having attained Grade 7–12, showed mixed effects in explaining HIV/AIDS self-testing uptake. Several barriers continue to limit the full adoption of HIV/AIDS self-testing with issues raised around the absence of counselling after testing, and challenges in the accurate use of HIV/AIDS kits compromising the reliability of the results. South Africa has a diverse population; thus, the provision of HIV/AIDS self-testing programmes should consider the context and culture of the target populations and that some population groups would prefer the use of self-testing kits to avoid the need for counselling which might be futile to them. HIV/AIDS self-testing uptake is correlated with interpersonal, sociocultural, and economic factors in mostly nonlinear ways because it is context related. Therefore, future research should be aimed at using spatial statistics and other various statistical techniques that include the spatiotemporal dimension and exploring other factors that influence HIV/AIDS self-testing uptake across South Africa. This will in turn enable meaningful and geotargeted interventions, thus making better use of limited resources.


For all participants, multichannel electrogastrography (EGG) with water-load testing and bioelectric impedance body composition analysis were done at baseline, after three months, and at six months. In the BS group, the water-load volume was decreased but without improvement in the bradygastria. In the LS group, preprandial bradygastria were reduced and some postprandial normogastria were increased throughout the study period. Except for fat-free mass and total body water, the parameters of body composition changes were superior in the BS group. In the LS group, the amount of fat-mass loss was negatively correlated with bradygastria times and positively correlated with preprandial and the early postprandial average dominant frequency (ADF). In addition, in the BS group, fat-mass loss was positively correlated with the ADF at late postprandial times. In conclusion, compared to BS, LS produced moderate normalization of GMA with the preservation of fat-free mass. The GMA changes were significantly associated with the amount of fat loss, regardless of the method of obesity management.The capability of bariatric surgery (BS) and lifestyle intervention (LSI) in ameliorating obesity-associated altered gastric myoelectric activity (GMA) in relation to body composition is underinvestigated. This work studied GMA during weight loss via sleeve gastrectomy and multimodal lifestyle intervention. Seventy-nine participants with morbid obesity were assigned into three groups: bariatric surgery (BS group,  The foundational step in obesity management is lifestyle intervention (LSI), including diet, increased physical activity, and behavioral modification. For patients who struggle with weight loss via LSI, adding medications that have been approved for chronic weight management is required . For resObesity has been linked to several comorbidities and chronic diseases , includiMeasuring GMA via multichannel transcutaneous electrogastrography (EGG) is a promising clinical procedure, especially with advanced technology devices that have received FDA approval. The hypothesis that “amelioration of obesity-induced GMA disturbances may be a mechanism of weight loss after BS” is a growing area of research. One study evaluated 20 patients undergoing laparoscopic non-adjustable gastric banding for 24 h, but GMA changes were insignificant . AnotherDespite the disappointing early reports, it is logical that BS can induce changes in GIT motility that are a direct effect of or secondary to an amelioration of previously obesity-induced disorders. Alterations of GMA and GIT motility are usually part of the mechanism of action and a result of BS . The stuBody composition changes after BS versus LSI are frequently studied . Howevern = 30), lifestyle intervention , and bariatric surgery   under reference number 49-2021-IRB, dated 3 June 2021. This study was also registered in ClinicalTrials.gov (record identifier is NCT05775172).Seventy-nine participants were divided into three groups: waitlist control  . The comFor participants in the BS group, laparoscopic sleeve gastrectomy was performed under general anesthesia. The same surgery team from the SBAHC medical center managed all cases. The routine surgical preparation, procedures, and postoperative care (including a dietary regimen for BS patients) were carried out. Baseline measurements were taken during the preoperative preparation workout (a few days before the surgery date); then. every patient was given two post-operative appointments for the third month (third M assessment) and the sixth month (sixth M assessment), so that all study measurements could be carried out once again.For participants in the LS group, a baseline assessment was performed at the first visit before the start of the intervention; then, every patient was provided with a schedule of biweekly short appointments for follow-up and two long appointments for the third- month and sixth-month assessments. Lifestyle intervention included a balanced 500- to 1000-calorie-deficit diet, a personalized physical activity plan, and customized behavioral modification. Detailed LS interventions were carried out according to our previous publication .For the no-intervention control (C) group, three appointments were made for baseline, third M, and sixth M assessments without providing any weight loss instructions.GMA was measured for 10 min after fasting for about 10–12 h and then again after water loading for 30 min by using a multichannel electrogastrography (EGG) with a water-load satiety test  . EGG rec2), the fat-free mass index (FFMI = FFM/height2) [2 for women and 6.3 kg/m2 for men) [Weight, height, and body mass index were measured as usually reported. A multi-frequency segmental bioelectric impedance analyzer  was used to analyze body composition. The parameters used for analysis included percentage body fat (PBF), fat mass (FM), fat-free mass (FFM), the fat-mass index  was used for all analyses.The Shapiro–Wilk test was used to test the normality of the study variables. The study parameters were compared among study groups by one-way ANOVA and Tukey’s HSD test for post hoc analysis or by a Kruskal–Wallis H test with the intergroup comparisons with the Mann–Whitney U test. Repeated measurements were assessed by Friedman’s ANOVA with Kendall’s coefficient of concordance for multiple comparisons of all pairwise. p > 0.5). Apart from a lower percentage of normogastria in the LS group, other parameters, including water-loading volume, were insignificantly different among the three groups.A comparison of the baseline assessment of the three groups is shown in At the date of the six-month assessment, some dropouts occurred—e.g., the C group had 30% no-shows, the LS group had 9% no-shows, and the BS no-show percent was 14.8%. The main causes of the dropouts were lack of interest (33%), especially in the C group, and living outside Riyadh (75%), especially in the BS group. The water-loading gastric volume was significantly lower in the BS group . HoweverIn the BS group, water-load volume reduced after three months with no additional significant reduction at the six-month assessment , while bThe condition of the BS group was different—i.e., apart from an increment of the Min20 duodenal rhythm at the six-month assessment, other parameters did not change. In summary, BS reduced the gastric volume and slowed down the high duodenal rhythm pattern, while LS kept the gastric volume stable but reduced the bradygastria time and increased the normogastria time.A comparison of the third-month and sixth-month assessments with the baseline body composition parameters is shown in As shown in p < 0.05). Furthermore, the amount of weight loss showed a positive correlation with the percentages of duodenal rhythm and tachygastria times, as well as a negative correlation with the percentage of bradygastria times  without significantly improving the bradygastria status . While LSI failed to reduce gastric volumes, LSI produced some significant improvement in bradygastria and normogastria times. Regarding BS, the previous reports of Gürlich et al. , van DieCrittenden et al.  used EGGContrary to our findings, Robertson et al.  comparedIn other disease populations, Kim et al.  used EGGTo the best of our knowledge, this is the first work studying the effect of multimodal LSI, including diet, physical activity, and behavioral modification, on EGG prospectively. However, some previous reports investigated the effect of physical activity on only EGG . Lu et al.  found thp < 0.05). In the BS group, the means of the ADF-20 and the ADF-min30 were positively correlated with fat-mass loss . This may postulate a mechanism for GMA changes after weight loss, regardless of the method. The normalization of GMA by surgery or successful LS intervention may work peripherally to reduce the amount of food intake and modulate gastric emptying, as well as centrally via gastric-brain coupling to affect satiety. Rebollo et al. [This study showed greater improvement in body composition parameters in the sleeve gastrectomy group than in the LS group. A recent meta-analysis concluded that sleeve gastrectomy leads to changes in weight loss, fat-mass loss, and lean-mass loss that are similar to the changes following a Roux-en-Y gastric bypass (RYGB). Moreover, RYGB led to a greater total-weight loss, greater fat-mass loss, and similar lean-mass loss than gastric banding . Anothero et al.  found tho et al. .Despite some of the strengths of this article, we encountered some limitations. The main limitation was the uneven dropout rate. High dropout rates are frequent in prospective studies of obesity management over a long period . AnotherIn the BS group, gastric volume was decreased but without improvement in the state of bradygastria. In the LS group, preprandial bradygastria percentages were reduced and some postprandial normogastria percentages were increased throughout the study period. Fat mass and percent of excess fat losses were superior in the BS group. Despite the superior weight-losing effect of BS, LS produced moderate normalization of GMA with the preservation of fat-free mass. GMA changes were significantly associated with the amount of fat loss, regardless of the method of obesity management.


We aimed to examine the risk of bleeding in female patients undergoing intravesical onabotulinumtoxinA (BTX-A) treatments and provide clinical recommendations for the perioperative management of patients on antithrombotic therapy prior to BTX-A treatments.This was a retrospective cohort of Danish female patients, who had their first BTX-A treatment because of an overactive bladder at the Department of Gynecology and Obstetrics, Herlev and Gentofte University Hospital, between January 2015 and December 2020. Data extraction was from an electronic medical journal system. BTX-A, Botox® Allergan was injected in the detrusor at 10–20 sites. Significant bleeding during or after a BTX-A treatment was defined as persistent macroscopic hematuria. Bleeding reporting was based on information obtained from journal notes.n=111) received antithrombotic therapy. Within this group, 30.6% and 69.4% were on anticoagulant and antiplatelet therapy. No cases of hematuria were reported in our cohort. We found that no patients stopped their antithrombotic therapy, were bridged, or monitored by International Normalized Ration (INR) levels.We included 400 female patients, who had a total of 1,059 BTX-A treatments. Median age at first BTX-A treatment was 70 years (IQR 21), and median number of BTX-A treatments was 2 (range 1–11). In total, 27.8% (We suggest that BTX-A treatments might be classified as low-risk procedures. Discontinuation of antithrombotic therapy is not required in the perioperative management of this patient group. Intradetrusor onabotulinumtoxinA (BTX-A) injections are a well-established treatment for overactive bladder. The injections are performed intravesically with a needle in 10–20 sites in the detrusor under cystoscopic guidance [It is an invasive procedure that can potentially result in bleeding complications. The risk of perioperative bleeding, in general, is increased in patients of older age >65 years), patients with cardiovascular and cerebrovascular diseases, abnormal renal or liver function, and on certain medicines , 3. Risk years, pApproval of our retrospective cohort study was obtained from Capital Region’s Knowledge Center for Data reviews (ID: R-21013125). Data extraction of our cohort of female patients, who had their first BTX-A treatment at the Department of Gynecology and Obstetrics, Herlev and Gentofte University Hospital between January 2015 and December 2020, was from the Danish electronic medical journal system “Sundhedsplatformen” by a data specialist. Patient data including demographics, medical history, antithrombotic therapy and indication, number of BTX-A treatments, information on bridging, International Normalized Ratio (INR) monitoring, and bleeding reporting were reviewed. All collected data were stored in the online database Research Electronic Data Capture (REDCap).Female patients over 18 years of age referred for treatment with BTX-A injections owing to an overactive bladder in our Urogynecology Clinic were identified.Patients were treated with BTX-A, Botox® Allergan. BTX-A was injected into the detrusor at 10–20 sites sparing the trigone under cystoscopic guidance. The treatments were performed in an operating theater or at our outpatient clinic, depending on the requirement for sedation during the injections.Significant bleeding during or after a BTX-A treatment was defined as persistent macroscopic hematuria. Easy bleeding from the injection sites may occur but usually ceases during the BTX-A injection procedure, causing no significant hematuria.Patients undergoing BTX-A treatments are routinely informed to contact our outpatient clinic if they experience any adverse effects, including bleeding. Follow-up related to assessment of post-void residual volume is scheduled for some patients, whereas no specific follow-up of bleeding is scheduled routinely. Bleeding reporting was based on information obtained from journal notes in the medical records.Patients on antithrombotic therapy were divided in two groups depending on the administered antithrombotic agent, anticoagulant (AC), and antiplatelet (AP) therapy respectively.Descriptive statistics were performed in R Studio, version 2022.07.1. Age and number of treatments were reported in median, interquartile range (IQR), and range. In this analysis, we assessed rates of antithrombotic therapy, antithrombotic agents, and the primary outcome, bleeding.n=111) of patients received antithrombotic therapy during their first BTX-A treatment. Seven different antithrombotic agents were registered, as listed in Table We included 400 consecutive female patients who had intravesical BTX-A treatments. Baseline characteristics are listed in Table We found no cases of bleeding in a Danish retrospective cohort comprising 400 female patients, who underwent between 1 and 11 BTX-A treatments for an overactive bladder at our Urogynecology Clinic. Within this cohort, 27.8% of patients were on antithrombotic therapy. Our results demonstrate that BTX-A treatments constitute a low bleeding risk. A previous Cochrane review concluded that intravesical BTX-A treatments are safe, with few adverse effects and complications, thereby supporting our results –11. One We found that none of the patients in our cohort discontinued their antithrombotic therapy prior to BTX-A treatments, according to the medical record. A plausible explanation could be that the procedure in our department is considered safe from a clinical perspective. However, antithrombotic therapy challenges the perioperative management of this patient group, and international consensus on this clinical matter is lacking. Older patients on antithrombotic therapy are at a higher risk of thromboembolic events and complications, including bleeding , and disAmong patients on antithrombotic therapy, we found that 69.4% were administered AP agents. The ESC recommends that continuation of the AP agent aspirin should depend on the perioperative bleeding risk compared with the risk of thrombotic complications . GuideliFor the prevention of a perioperative thromboembolism during discontinuation of AC therapy, a bridging therapy strategy can be used. Bridging therapy refers to the use of short-acting ACs, including unfractionated heparin or low-molecular-weight heparin . We founThe bleeding risk associated with BTX-A treatments is not well described, and to our knowledge no guideline is available on the management of patients on antithrombotic therapy undergoing this procedure, emphasizing the need for recommendations.Based on our findings and the available literature, we suggest that BTX-A treatments might be classified as low-risk surgical procedures with regard to bleeding complications. As the benefits of antithrombotic therapy are likely to outweigh the risk of bleeding, demonstrated by no reported bleeding case in our cohort, we suggest continuing antithrombotic therapy in female patients undergoing a BTX-A treatment. BTX-A treatments are frequently performed at our Urogynecology Clinic, and the number is increasing. Our results can support the development of a clinical practice guideline concerning the perioperative management of antithrombotic therapy, including counseling, in this patient group. Nevertheless, physicians should assess patients individually in the case of a history of procedure-related bleeding.In the event of bleeding, treatment is accessible. Common treatments of hematuria in urogynecological patients include urethral catheterization with a two-way catheter and saline bladder irrigation. Bleeding management at the operating theatre could be indicated in the case of failed conservative treatment, or a hemodynamically unstable patient.Our study has some limitations. We may have underestimated the bleeding risk and missed some cases of bleeding, as any events relied on self-reporting from the patients. Patients are informed to contact the Urogynecology Clinic in the event of bleeding. No systematic reporting or follow-up on bleeding has been established. The retrospective nature of the study contributes to limitations as well. Inconsistent reporting in the medical record by medical staff could also contribute to missing data on bleeding cases. Selection bias was avoided by including 400 consecutive female patients in the study period.We have demonstrated that the risk of hematuria requiring treatment after BTX-A injections is low in female patients on antithrombotic therapy. Thereby, BTX-A treatments are a low-risk surgical procedure, and we suggest that antithrombotic therapy should not be discontinued during the perioperative management of this patient group.


Emotion regulation difficulties are associated with many neurological conditions and negatively impact daily function. Yet little is known about emotion regulation in adults with cerebral palsy (CP). Our aim was to investigate emotion regulation in adults with CP and its relationship with condition-related and/or socio-demographic factors. In a cross-sectional study of adults with CP, participants completed a survey containing the Difficulties in Emotion Regulation Scale (DERS), Depression Anxiety and Stress Scale-21 (DASS-21), and socio-demographic and condition-related questions. Descriptive statistics, chi-squared and Mann–Whitney tests were performed. Of the 42 adults with CP  that were tested, 38 had within normal limits DERS total scores; however, a significantly higher proportion of participants experienced elevated scores  than would be expected in the general population across five of the six DERs subdomains. Moderate–extremely severe depression and anxiety symptoms were reported by 33% and 60% of participants, respectively. The DERS total scores for participants with elevated depression, anxiety, and stress scores were significantly higher than the DERS totals score for those without elevated depression, anxiety, and stress scores. DERS and DASS-21 scores did not differ significantly by condition-related nor socio-demographic characteristics. In conclusion, emotion regulation difficulties were associated with elevated symptoms of depression and anxiety, which were overrepresented in the adults with CP participating in this study. Cerebral palsy (CP) is an umbrella term for a group of non-progressive motor disorders resulting from damage to or maldevelopment of the immature brain . These dEmotion regulation (ER) refers to how we ‘influence which emotions we have, when we have them, and how we experience and express them’ . It invoER difficulties are associated with a range of conditions. More than half of all psychological diagnostic categories  and all personality disorders include ER difficulties as part of the symptomatology required to meet diagnostic criteria ,12. ER dThe neural underpinning of ER is also important to examine when considering the likelihood of associations between ER difficulties and CP in adulthood. A model proposed by Etkin et al. 2015) describes how predictions, prediction errors, and valuations contribute towards two forms of ER: model-free regulation and model-based regulation . However describeResearch is required to better understand ER and the relationship between ER and clinical and socio-demographic factors in adults with CP. This is necessary to determine whether there is a need for services and screening to support adults with CP and to assist in managing these challenges. In this study, we aimed to (1) investigate self-reported ER difficulties in adults with CP, and (2) to determine whether ER was associated with other demographic and condition-related factors, including symptoms of mood difficulties , ambulatory status, communication level, living arrangements, employment status, etc. It was hypothesised that (1) adults with CP are more likely to experience ER difficulties than the general population, and (2) that ER difficulties are associated with mood and condition-related factors and socio-demographic factors such as ambulatory status and employment status, respectively.This was a cross-sectional study design. The research question was initiated by co-author FG who has a lived experience of CP. Key stages of study design and interpretation of results were informed by lived experience and current best research practice. Methodology and data are reported according to the CHERRIES (Checklist for Reporting Results of Internet E-Surveys) statement .Ethical approval was granted by the Cerebral Palsy Alliance Human Research Ethics Committee (3 November 2018), Victorian Cerebral Palsy Register Governance, and Queensland Cerebral Palsy Register Steering Committee, with data collected throughout 2019. All participants were provided a participant information sheet outlining study protocol and informed consent was obtained.The study was advertised in the NSW/ACT CP Register newsletter and via a study flyer . To be eParticipants completed a voluntary 15-min paper or online survey. The survey included questions related to socio-demographic and clinical condition, including gender, age, residential postcode, employment status, living arrangements, primary support person, Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R)  level, pOther items included the Depression Anxiety and Stress Scale short-form (DASS-21)  and the DERS is a validated 36-item self-report measure of emotion regulation. Using a five-point Likert scale 1–5  participants rate responses. Responses were tallied to obtain a total score and six sub-scale scores: non-acceptance of emotional responses (nonaccept), difficulties engaging in goal directed behaviour , impulse control difficulties (impulse), lack of emotional awareness (awareness), limited access to ER strategies (strategies), and lack of emotional clarity (clarity) . Higher Online open survey data were collected using REDCap electronic data capture tool, hosted by The University of Sydney. A response was required for all items on the DASS-21 and DERS and participants were able to progress through the survey and review their previous responses at their own pace. The survey was completed by five individuals prior to study commencement to review functionality and acceptability. A copy of the survey is available in Employment was collapsed into two categories based on participant responses: ‘Employed’ = full-time, part-time, casual, volunteer, student; ‘Unemployed’ = unemployed, retired. Similarly, living situation was collapsed into four categories: ‘Alone’; ‘Share house’ = share house or supported accommodation; ‘With spouse’ = with or without children; ‘Other family’ = living with parents, living with other children alone or living with other family. GMFCS was collapsed into two categories: ‘Ambulant’ = GMFCS level I or II; ‘Supported mobility’ = GMFCS levels III, IV and V. DASS-21 scores were categorised into normal, mild, moderate, severe, and extremely severe groups . Scores p = 0.05. Mean total DERS T-scores by DASS-21 sub-scale category were calculated and plotted onto a bar graph. Where sample sizes allowed (n ≥ 5), Mann–Whitney tests were performed to examine relationships between clinical and socio-demographic factors and DASS-21 and DERS scores.Data were analysed using SPSS (Version 24). Descriptive and frequency statistics were run for all variables. Means and proportions were calculated for DASS-21 and DERS sub-scales, and chi-squared tests were performed on DERS scores to compare whether the current sample proportions differed from expected population proportions, based on normative data. Mann–Whitney tests were conducted to examine the relationship between Total DERS scores and DASS-21 sub-scales, with significance set to n = 42 participants with complete data which were included in the analyses. After eliminating any duplicate responses, there were 48 respondents who participated in the survey; two were ineligible, two declined consent, and two were incomplete. There were n = 24/42 (58%) of participants were living with other family members, with the majority of this group living with their parents. Seventy percent of participants were engaged in some form of employment (including volunteer work or study); however, only 22.5 percent of participants were working full-time. Just over 40 percent of participants had received a formal diagnosis of a psychological disorder.The mean age of participants was 31.5 years (SD 13.48) and 43 percent were males. The majority of participants had spastic hemiplegia and were ambulant . Most paExamination of self-reported ER using the DERS found that only four participants reported experiencing total elevated DERS scores. Due to small sample size in the elevated group, it was not possible to examine statistical significance. However, when examining sub-scale scores, a higher proportion of participants experienced elevated scores across all sub-scale areas, except lack of emotional clarity, than would be expected in the general population .When examining results from the DASS-21  the dataThere was a significant positive relationship between depression, anxiety, and stress, and total DERS scores. DERS total scores for participants with elevated depression, anxiety, and stress scores was significantly higher than the DERS totals score for those without elevated depression, anxiety, and stress scores .When examining DERS total T-scores, depression, anxiety, and stress scores by gender and employment status, there were no significant differences across groups . SimilarTo date, there has been little research investigating ER in adults with CP. To begin to explore these factors we conducted a cross-sectional survey of adults with CP with no/mild intellectual impairment. Self-reported ER scores varied widely, with 90% of participant total scores falling within normal limits. However, when examining ER sub-scale scores, a higher proportion of participants scored in the elevated range across all sub-scales, except emotional clarity, than would be expected in the general population. Worryingly, moderate-extremely severe symptoms of depression and anxiety were common; however, most participants’ stress scores fell within normal limits. A clear positive relationship was observed between mood and ER scores, whereby people with elevated depression, anxiety, and stress scores experienced more ER difficulties than those without elevated depression, anxiety, and stress scores. Apart from having a diagnosed psychological disorder, no other clinical or socioeconomic factors were associated with the DERS or DASS-21 scores in this sample.n = 10, 24%), difficulties engaging in goal-directed behaviour , impulse control difficulties , lack of emotional awareness , and limited access to ER strategies . Lower acceptance of emotions, not having strategies, or using less effective ER strategies have been associated with higher depressive symptoms [A statistically significant proportion of the total group had elevated sub-scale scores for nonacceptance of emotional responses  who reported having a diagnosed psychological disorder. This highlights a possible self-selection bias with participants who are aware of, or who are experiencing difficulties in this area of their lives potentially being more likely to respond to the study invitation. Conversely, there may have been an underrepresentation of participants with psychological and emotion regulation difficulties who may have chosen not to participate. Finally, the survey was sent to everyone within the eligible age range on the CP registers. The response rate of 42, although expected for a survey study with no immediate benefit for participants, is low. Results, therefore, may not be representative of the broader CP in adulthood population. Finally, data were collected in 2019 before the COVID-19 pandemic. Marginalised groups, including people with disability, have been disproportionately negatively affected by the COVID-19 pandemic and associated societal and policy changes [To the best of our knowledge, this is the first study to investigate the relationship between ER, mood, and socio-demographic and condition related factors in adults with CP. The research question for this study was originally initiated by author FG who has a lived experience of CP. We found that adults with CP in this study had increased experiences of emotional dysregulation than the general population, had elevated symptoms of depression and anxiety, and that increasing symptoms of depression, anxiety, and stress were associated with poorer emotion regulation. In terms of limitations, this was a preliminary study which aimed to examine ER across adults with CP, and no matched comparison group was included in the design. We did not specifically target any CP motor subgroups for recruitment. The small number of respondents meant it was not statistically viable to investigate ER or mood in some subgroups of interest. Future studies could specifically recruit a sample of adults with dyskinetic CP to investigate emotion dysregulation and mood disorders amongst adults with dyskinetic CP, given dyskinetic CP frequently involves damage to the basal ganglia . As data changes . SimilarThis is the first study investigating ER amongst adults with CP. Here we observed that the majority of participants had total ER scores within normal limits. However, more participants than expected based on the general population had elevated sub-scale scores, indicating difficulties accepting emotional responses, engaging in goal-directed behaviour, controlling impulses, a lack of emotional awareness, and low belief in and knowledge of strategies to help regulate emotions. Worryingly, a higher proportion of participants reported symptoms of depression than the general population and a relatively high proportion reported symptoms of anxiety. In this study, we found a clear positive relationship between mood and ER scores, whereby participants with elevated depression, anxiety, and stress symptoms reported more ER difficulties than those who did not have elevated depression, anxiety, or stress symptoms. Considering the relationship between mood and ER, use of ER strategies  may be helpful tools for people with CP and mood difficulties. In the absence of known prevention strategies, screening of emotion regulation and mood difficulties as part of routine health reviews with appropriate onward referral and support should be evaluated.


Editorial on the Research TopicPathophysiological and clinical insights for atrial fibrillation/flutter or heart failureGeriatric atrial fibrillation (AF) and atrial flutter (AFL) frequently coexist and complicate each other's treatment. Anti-arrhythmic drugs may not be effective, and cardioversion to sinus rhythm may be necessary. Anticoagulation therapy's side effects are also worthy of attention. Recent techniques, such as left atrial appendage occlusion, are becoming attractive for AF/AFL management. Novel drugs targeting specific ion channels are also being investigated. Despite progress in geriatric AF/AFL or heart failure (HF), their mechanisms and treatments require further investigation. The current research topic includes 13 studies on current advancements in mechanisms and treatment options for geriatric AF/AFL or HF.Hou et al. found that a decreased change in N-terminal pro-brain natriuretic peptides (NT-proBNP) may improve survival outcomes and prevent severe AKI in elderly patients with CHF. However, an excessive decrease in NT-proBNP can increase the risk of non-recovery of renal function following AKI.Elderly patients have a higher incidence of chronic heart failure (CHF), which can lead to acute kidney injury (AKI) and poor prognosis. In a retrospective cohort study, Liu et al. conducted a retrospective cohort study and found that the addition of tolvaptan (TLV) effectively increased urine output and had favorable effects on alleviating AHF progression. TLV may also reduce the risk of all-cause mortality in elderly patients with AHF and oliguria.In elderly patients with acute heart failure (AHF) and oliguria, high doses of loop diuretics are often ineffective and may adversely affect prognosis. Saglietto et al.). In particular, the ventricular response is completely irregular during AF, while generally regular during AFL, and their pathophysiology is different. The AF-related beat-to-beat variability alters deep cerebral microvascular perfusion as it induces transient and repetitive hypoperfusion or hypertension. A differential risk of dementia between AF and AFL was found in a national cohort study  which leads to reversible HF for many years. However, the knowledge of TCM is still limited. Pradhan et al. revealed that under tachyarrhythmic conditions, miR-21-5p is released in-vitro from cardiomyocytes and stimulates collagen production by fibroblasts in a paracrine mode.Atrial fibrosis represents a major hallmark in the disease progression of AF. Circulating microRNA-21 (miR-21) has been validated as a biomarker that reflects the extent of left atrial fibrosis in AF patients. Furthermore, He et al. found that a combination of age, atrial premature beats, atrial flutter, left ventricular hypertrophy, hypertension, and heart disease may be used to screen high-risk individuals for AF episodes.AF is prone to HF and stroke. Early management can effectively reduce the stroke rate and mortality. In a population of 18,738 elderly people (aged over 60 years old) in Chinese communities, Guo et al., elderly Chinese patients with AF are generally multimorbid and polypharmacy. They also report a high rate of inappropriate prescribing. The ABC -bleeding risk score may be useful in assessing the risk of major bleeding in Chinese patients with AF on oral anticoagulation therapy in real-world practice, and they suggest that this score performed better in stratifying patients with a high risk than the modified HAS-BLED score .According to Zhu et al.).The angiotensin receptor-neprilysin inhibitor (ARNI) is a potential upstream treatment option for AF. ARNI could reduce atrial electrical instability in AF in comparison with ARB in both retrospective studies and animal experiments  showed that AF recurrence after CA is more likely in patients with large LAA structures  and decreased LAA function prior to ablation .The left atrial appendage (LAA) and structure may be predictors of AF recurrence after CA, but the results of studies evaluating them are contradictory. A meta-analysis ; however, it is unclear how these areas affect recurrence after CA. According to Zhao et al. displayed that DAT could be a feasible and safe method to deal with APT during the AF-CA procedure.AF-CA is associated with a number of serious complications, including acute pericardial tamponade (APT). In pericardial autotransfusion (DAT), pericardial blood is injected directly into patients' veins without a cell-salvage system. There is limited information available regarding DAT for APT. Tashiro et al., PD is independently associated with an increased risk of arrhythmia recurrence after the first CA for paroxysmal atrial fibrillation.Inflammatory conditions such as periodontitis (PD), a chronic inflammatory disease, may contribute to the development of AF. According to As a whole, the current Research Topic provides up-to-the-minute information on many aspects of pathophysiology and clinical considerations associated with AF/AFL or HF. New perspectives may emerge as a result of more comprehensive knowledge based on these discoveries.


The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of cleft lip and/or palate (CL/P) care in low- and middle-income countries (LMICs) based on existing literature.We searched eleven electronic databases for articles from January 1, 2000 to December 29, 2020. This study is registered in PROSPERO (CRD42020148402). Two reviewers independently conducted primary and secondary screening, and data extraction.All CL/P cost-effectiveness analyses in LMIC settings.In total, 2883 citations were screened. Eleven articles encompassing 1,001,675 patients from 86 LMICs were included.We used cost-effectiveness thresholds of 1% to 51% of a country's gross domestic product per capita (GDP/capita), a conservative threshold recommended for LMICs. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) checklist.Primary CL/P repair was cost-effective at the threshold of 51% of a country's GDP/capita across all studies. However, only 1 study met at least 70% of the JBI criteria. There is a need for context-specific cost and health outcome data for primary CL/P repair, complications, and existing multidisciplinary management in LMICs.Existing economic evaluations suggest primary CL/P repair is cost-effective, however context-specific local data will make future cost-effectiveness analyses more relevant to local decision-makers and lead to better-informed resource allocation decisions in LMICs. Yet, CL/P is undertreated in low- and middle-income countries (LMICs). Untreated children with CL/P experience malnutrition, poor dentition, ear infections, speech deficiencies, and extreme social stigma which has resulted in abandonment or infanticide. Cost-effectiveness analyses are used to compare the value of interventions, and prioritized interventions in LMICs are those that are cost-effective and feasible. The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of CL/P care in LMICs based on existing literature. This will consolidate existing decision-analyses for CL/P in LMICs and assess the methodologic quality of these analyses in how they can be used to help inform LMIC resource allocation decisions.Economic evaluations help clinicians and policymakers make informed decisions in resource-constrained settings.Appendix 1). The search strategy was designed and executed by an Information Specialist (JB) with expertise in systematic reviews with additional clinical input (KC).This systematic review is conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The fulWe searched 11 electronic databases from January 1, 2000 to December 29, 2020 using keywords and medical subject headings related to the following concepts: cleft lip, cleft palate, cost-effectiveness, and economic evaluations. The search strategy was initially developed in Ovid MEDLINE, and then adapted to the syntax and subject headings of the other databases: Global Health Cost-Effectiveness Analysis Registry, Cost-Effectiveness Analysis (CEA) Registry, Ovid EMBASE, Global Index Medicus, ScHARRHUD database, Cochrane Database of Systematic Reviews database, and the Center for Reviews and Dissemination Databases, which includes the Health Technology Assessment Database (HTA), HTA Database Canadian Repository, the NHS Economic Evaluation Database (NHS EED) and the Database of Abstracts of Reviews of Effects. Additionally, we hand-searched gray literature and bibliographies of identified publications. Finally, we searched PROSPERO for ongoing or recently completed systematic reviews. Only English language studies were included due to feasibility and resource constraints. We excluded studies that were not full economic evaluations, such as studies that reported only health outcomes, or cost-minimization, cost-consequence and cost-of-illness studies.Two reviewers  independently assessed the titles, abstracts, and full texts for inclusion using DistillerSR. Full economic evaluations that reported cost-benefit analyses, cost-effectiveness analyses, or cost-utility analyses of primary cleft lip and/or palate repair in LMIC settings as defined by the World Bank were included. These criteria are a validated international tool to evaluate evidence related to the feasibility, appropriateness, meaningfulness, and effectiveness of health care interventions.Two reviewers (KC and AE or GH) independently extracted data and conducted the quality appraisal using the Joanna Briggs Institute (JBI) critical appraisal tool for economic evaluations.6 For articles that provided summaries across countries and regions, we used the inflation rate for the specific region or the region with the highest volume of cleft surgeries, as appropriate. Cost-effectiveness analyses are composed of cost-utility analyses or cost-benefit analyses. Cost-utility analysis is a method of economic evaluation, where health outcomes are valued using a generic measure of health, such as Disability-Adjusted Life Years (DALYs). The results are reported as an Incremental Cost-Effectiveness Ratio of dollars per DALY averted. In cost-benefit analyses, health outcomes are valued in monetary terms and can be based on the Gross National Index per capita (GNI/capita) for each country.9 Surgeries performed in a country with a higher GNI/capita will thus report a higher economic benefit compared to surgeries performed in a country with a lower GNI/capita. The results are reported as a ratio of costs to benefits or as a net benefit or loss, and if they were based on disability weights from the Global Burden of Disease (GBD) study then these values may be adjusted by age-weighting at 4% and discounting at 3%.10 We assessed the cost-effectiveness of primary CL/P repair using cost-effectiveness thresholds of 1% to 51% of a country's gross domestic product per capita (GDP/capita), a conservative estimate of health spending recommended for LMICs.1113We reported costs in 2020 International Dollars (USD). Where country-specific costs were provided, these were inflated to the most recent year based on the country's consumer price index.10,1424 Four studies considered patients from a low-income country , Interplast (n = 2), Smile Train (n = 3), Smile for Children (n = 1), the Children's Surgical Center (n = 1), and Hands Across the World (n = 1). Age at surgery ranged from 142 days old to 74 years old. DALYs were derived from isolated cleft lip or isolated cleft palate disability weights produced by the GBD studies in 1990 or 2004 for ten of the 11 studies. The remaining study measured and applied disability weights based on the expertise of 5 surgeons. The other study used isolated cleft lip as a proxy for complications and included this in the DALYs averted for CL/P.The health impact of CL/P complications, i.e. fistula or lip/nose revision, was included in 2 studies. One study cited a disability weight of 0.05 for both the palatine fistula and the lip revision.All studies reported costs in international dollars (USD). Costs regarding whether NGOs used a center- or mission-based approach are outlined in Ten of the 11 articles valued health outcomes in terms of DALYs. DALYs averted per cleft lip or palate repair ranged from 1.2 to 10.7, dependent on the country . The cosSix cost-benefit analyses were reported, all of which used the human capital approach . Using tAll articles met at least 1 of the 11 JBI criteria . However1113 Based on this threshold, the cost per DALY for primary CL/P repair was cost-effective across all studies. However, several concerns were identified that could limit this implication.This systematic review synthesizes the evidence on the economic value of CL/P repair in LMICs to date. All studies reported the costs of CL/P repair from the health care payer perspective, where the health care payer was the NGO. Local governments can assume the role of the health care payer and consider whether CL/P repair is cost-effective for their country. A cost-effectiveness threshold of up to 51% of the GDP/capita is recommended for LMICs.2628 Further, GBD descriptions do not include difficulties swallowing, malnutrition, and the extreme social stigma experienced by patients with CL/P in LMICs. Finally, disability weights for surgically treated CL/P were last estimated in 1990, by a small panel of elite international health experts and there is no consideration of multidisciplinary management. Second, all studies reported costs from the NGO perspective and thus the costs from the government perspective are unknown. Further, none of the studies considered opportunity costs for patients and their caregivers in receiving treatment. These context-specific costs can better inform cost-effectiveness analyses in these settings. Third, 10 of the 11 papers did not consider disability weights for untreated patients with combined cleft lip and palate. Cleft lip and palate is considered more severe than isolated cleft lip or cleft palate, and studies that omit this may further underestimate the burden of disease and cost-effectiveness of CL/P repair. Fourth, there was limited consideration of complications which may result from surgery, and finally, none of the articles considered multidisciplinary management.First, it is suspected that GBD disability weights underestimate the disease severity and impact of treatment. Disability weights are considered ‘universal’; however, they came from international societal participants, a sample heavily skewed to those from high-income countries (HICs).Due to these concerns, existing CL/P cost-effectiveness analyses for LMICs may have underestimated the severity of CL/P and the impact of treatment. The main strength of this study is that it synthesizes existing evidence to highlight what is needed to better represent the cost-effectiveness of CL/P care and inform subsequent resource allocation decisions in LMICs. The main limitation of this systematic review is that we excluded 71 articles that were not published in English. However, none of these studies appeared to be relevant for CL/P economic evaluations when these articles were screened using an online translation tool. Thus, for policy decision-makers to make informed decisions in allocating public funds, cost-effective analyses are critical. The lack of context-specific health and cost data reported from LMICs is a limitation seen with existing economic evaluations for other surgical diseases. Utilities are an alternative to disability weights and are recommended for cost-effectiveness analyses for HICs.30 Utilities are intended to be context-specific, reported from the patient or societal perspective, and can account for health equity.30, However, utilities in LMICs are scarce compared to those in HICs. This is especially the case for surgical diseases relative to pharmaceutical interventions and the lack of context-appropriate utilities for these populations can further disadvantage them in LMIC resource allocation decisions. Thus, opportunities exist for further investigations that consider utilities, costs, complications, and multidisciplinary management for CL/P from LMIC participants to provide the context-relevant data that is currently missing. Collaborations to provide this evidence can help inform decisions that can lead to a sustainable, multidisciplinary, and longitudinal standard of surgical care that is acceptable in HICs.Thanks to efforts from the Lancet Commission of Global Surgery, the 68th World Health Assembly passed the resolution on including surgery as a component of Universal Health Coverage.Existing economic evaluations suggest primary CL/P repair is cost-effective, however, there is a need for context-specific cost and utility data for primary CL/P repair, complications, and existing multidisciplinary management in LMICs. Context-specific local data will make future CEAs more relevant to local decision-makers and lead to better-informed resource allocation decisions in LMICs.Click here for additional data file.Supplemental material, sj-docx-1-cpc-10.1177_10556656221111028 for A Systematic Review of the Cost-Effectiveness of Cleft Care in Low- and Middle-Income Countries: What is Needed? by Karen Y. Chung, George Ho, Aysegul Erman, Joanna M. Bielecki, Christopher R. Forrest and Beate Sander in The Cleft Palate Craniofacial Journal