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Introduction: The prevailing theories of consciousness consider the integration of different sensory stimuli as a key component for this phenomenon to rise on the brain level. Despite many theories and models have been proposed for multisensory integration between supraliminal stimuli (e.g., the optimal integration model), we do not know if multisensory integration occurs also for subliminal stimuli and what psychophysical mechanisms it follows. Methods: To investigate this, subjects were exposed to visual (Virtual Reality) and/or haptic stimuli (Electro-Cutaneous Stimulation) above or below their perceptual threshold. They had to discriminate, in a two-Alternative Forced Choice Task, the intensity of unimodal and/or bimodal stimuli. They were then asked to discriminate the sensory modality while recording their EEG responses. Results: We found evidence of multisensory integration for supraliminal condition, following the classical optimal model. Importantly, even for subliminal trials participant's performances in the bimodal condition were significantly more accurate when discriminating the intensity of the stimulation. Moreover, significant differences emerged between unimodal and bimodal activity templates in parieto-temporal areas known for their integrative role. Discussion: These converging evidences - even if preliminary and needing confirmation from the collection of further data - suggest that subliminal multimodal stimuli can be integrated, thus filling a meaningful gap in the debate about the relationship between consciousness and multisensory integration.
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Background: Acupuncture is a widely practiced complementary and integrative health modality that has multiple clinical applications. The use of acupuncture in the United States is rapidly increasing. Although studies have shown the efficacy and effectiveness of acupuncture for various ailments, the integration of acupuncture into the U.S. health care system remains a challenge. Little is known about the factors affecting this integration. Objective: To provide a systematic review of the barriers and facilitators affecting the integration of acupuncture into the U.S. health care system. Methods: Four electronic databases were searched. Three independent reviewers were involved in the screening and data charting processes. Findings were synthesized and categorized into four levels based on the Social Ecological Model. Results: A total of 22 studies were included in the final review. The barriers and facilitators affecting the integration of acupuncture were mapped into four levels (individual, interpersonal, organizational, and policy). The most frequently reported barriers and facilitators were mapped into the Social Ecological Model constructs within the "Individual" level (i.e., beliefs and attitudes of acupuncture, and practical issues) and the "Organizational" level (i.e., credentialing, space and facility, referral system). Conclusion: This review has identified and synthesized the breadth of evidence on the barriers and facilitators to the integration of acupuncture into the U.S. health care system. Results of this review will guide future implementation studies to develop and test implementation strategies to integrate acupuncture into the U.S. health care system.
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OBJECTIVE: To describe the use of privacy preserving linkage methods operationally in Australia, and to present insights and key learnings from their implementation. METHODS: Privacy preserving record linkage (PPRL) utilising Bloom filters provides a unique practical mechanism that allows linkage to occur without the release of personally identifiable information (PII), while still ensuring high accuracy. RESULTS: The methodology has received wide uptake within Australia, with four state linkage units with privacy preserving capability. It has enabled access to general practice and private pathology data amongst other, both much sought after datasets previous inaccessible for linkage. CONCLUSION: The Australian experience suggests privacy preserving linkage is a practical solution for improving data access for policy, planning and population health research. It is hoped interest in this methodology internationally continues to grow.
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There are no studies that have experimentally tested how temporal integration/segregation of sensory inputs might be linked to the emergence of dissociative experiences and alterations of emotional functioning. Thirty-six participants completed 3 sensory integration tasks. Psychometric thresholds were estimated as indexes of temporal integration/segregation processes. We collected self-report measures of pre-task trait levels of dissociation, as well as pre- post-task changes in both dissociation and emotionality. An independent sample of 21 subjects completed a control experiment administering the Attention Network Test. Results showed: (i) a significant increase of dissociative experiences after the completion of sensory integration tasks, but not after the ANT task; (ii) that subjective thresholds predicted the emergence of dissociative states; (iii) temporal integration efforts affected positive emotionality, which was explained by the extent of task-dependent dissociative states. The present findings reveal that dissociation could be understood in terms of an imbalance between "hyper-segregation" and "hyper-integration" processes.
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Adeno-associated viral vector (AAV) gene therapy provides a promising platform for treatment of monogenic inherited disorders. Clinical studies have demonstrated long-term expression with reduction in bleeding using this approach for the treatment of hemophilia. Despite these advances, there are unknowns surrounding the natural history of recombinant AAV (rAAV) vectors and the cellular mechanisms mediating vector persistence. These unknowns underpin questions regarding long-term efficacy and safety. The predominant mechanism via which AAV is proposed to persist is in circular double-stranded extrachromosomal DNA structures (episomes) within the nucleus. Studies of wild-type (WT-AAV) and rAAV have demonstrated that AAV also persists via integration into a host cell's DNA. It is important to determine whether these integration events can mediate expression or could result in any long-term safety concerns. WT-AAV infection affects a large proportion of the general population, which is thought to have no long-term sequelae. Recent studies have highlighted that this WT-AAV has been detected in cases of acute hepatitis in children and in a minority of cases of hepatocellular carcinoma. Integration following treatment using rAAV has also been reported in preclinical and clinical studies. There have been variable reports on the potential implications of integration for rAAV vectors with data in some murine studies demonstrating recurrent integration with development of hepatocellular carcinoma. These findings have not been seen in other pre-clinical or clinical studies. In this review, we will summarize current understanding of the natural history of AAV (wild-type and recombinant) with a focus on genomic integration and the cellular implications.
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BACKGROUND: Understanding the complex interactions between genes and their causal effects on diseases is crucial for developing targeted treatments and gaining insight into biological mechanisms. However, the analysis of molecular networks, especially in the context of high-dimensional data, presents significant challenges. METHODS: This study introduces MRdualPC, a computationally tractable algorithm based on the MRPC approach, to infer large-scale causal molecular networks. We apply MRdualPC to investigate the upstream causal transcriptomics influencing hypertension using a comprehensive dataset of kidney genome and transcriptome data. RESULTS: Our algorithm proves to be 100 times faster than MRPC on average in identifying transcriptomics drivers of hypertension. Through clustering, we identify 63 modules with causal driver genes, including 17 modules with extensive causal networks. Notably, we find that genes within one of the causal networks are associated with the electron transport chain and oxidative phosphorylation, previously linked to hypertension. Moreover, the identified causal ancestor genes show an over-representation of blood pressure-related genes. CONCLUSIONS: MRdualPC has the potential for broader applications beyond gene expression data, including multi-omics integration. While there are limitations, such as the need for clustering in large gene expression datasets, our study represents a significant advancement in building causal molecular networks, offering researchers a valuable tool for analyzing big data and investigating complex diseases.
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Algoritmos , Redes Reguladoras de Genes , Hipertensão , Aprendizado de Máquina , Hipertensão/genética , Humanos , Transcriptoma/genética , Perfilação da Expressão Gênica/métodos , Biologia Computacional/métodos , Análise por ConglomeradosRESUMO
The global burden of hepatitis B virus (HBV) infection remains high, with chronic hepatitis B (CHB) patients facing a significantly increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). The ultimate objective of antiviral therapy is to achieve a sterilizing cure for HBV. This necessitates the elimination of intrahepatic covalently closed circular DNA (cccDNA) and the complete eradication of integrated HBV DNA. This review aims to summarize the oncogenetic role of HBV integration and the significance of clearing HBV integration in sterilizing cure. It specifically focuses on the molecular mechanisms through which HBV integration leads to HCC, including modulation of the expression of proto-oncogenes and tumor suppressor genes, induction of chromosomal instability, and expression of truncated mutant HBV proteins. The review also highlights the impact of antiviral therapy in reducing HBV integration and preventing HBV-related HCC. Additionally, the review offers insights into future objectives for the treatment of CHB. Current strategies for HBV DNA integration inhibition and elimination include mainly antiviral therapies, RNA interference and gene editing technologies. Overall, HBV integration deserves further investigation and can potentially serve as a biomarker for CHB and HBV-related HCC.
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The question of whether free will exists or not has intrigued philosophers for centuries. About 40 years ago, cognitive neuroscientists such as Benjamin Libet have joined the discussion by demonstrating that an ERP component, the readiness potential (RP), precedes the reported time of decision to act by a few hundred milliseconds. Libet et al. (1983) argued that our brains unconsciously prepare the movement before we experience any conscious intention, which led some free will skeptics (e.g., Ebert & Wegner, 2011) to argue that free will does not exist. While Libet's interpretation of his findings initiated an intense philosophical debate, alternative interpretations have been put forward more recently (Bode et al., 2014; Brass et al., 2019; Schurger et al., 2012; 2021). Integration to bound models (ITB) of Libet-style experiments suggest that we accumulate information until an intention threshold is reached, which triggers our experience of intention and execution of voluntary behaviors. The RP, from this perspective reflects the decision process itself rather than the consequence of an unconscious decision. To determine if the ITB model better predicts behavioral patterns in Libet-style experiments, we added a whether-component to the classical Libet task (the Veto Libet task) and compared the behavioral measures in the Veto Libet task with the Classical Libet task. We hypothesized that the signal accumulation in the Veto Libet task would be less steep than in the Classical Libet task, resulting in longer wait times and earlier self-reported intentions to act (i.e., the W). The result in general supported our hypotheses. In addition, these behavioral differences between the Classical Libet task and the Veto Libet task established valuable behavioral correlates for future investigations into the vetoing phenomenon. Finally, this study was also the first application of the Libet task in an online setting, and the behavioral parameters were highly comparable to the previous offline studies, further supporting the possibility of using the online platform to study arbitrary decision-making.
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The label "deaths of despair" for rising US mortality related to drugs/alcohol/suicide seems to implicate emotional distress as the cause. However, a Durkheimian approach would argue that underlying structural factors shape individuals' behavior and emotions. Despite a growing literature on deaths of despair, no study has directly compared the effects of distress and structural factors on deaths of despair versus other causes of mortality. Using data from the Midlife in the United States study with approximately 26 years of mortality follow-up, we evaluated whether psychological or economic distress, employment status, and social integration were more strongly associated with drug/alcohol/suicide mortality than with other causes. Cox hazard models, adjusted for potential confounders, showed little evidence that psychological or economic distress were more strongly associated with mortality related to drugs/alcohol/suicide than mortality from other causes. While distress measures were modestly, but significantly associated with these deaths, the associations were similar in magnitude for many other types of mortality. In contrast, detachment from the labor force and lower social integration were both strongly associated with drug/alcohol/suicide mortality, more than for many other types of mortality. Differences in the estimated percentage dying of despair between age 25 and 65 were larger for employment status (2.0% for individuals who were neither employed nor retired versus only 0.6% for currently employed) and for social integration (1.9% for low versus 0.7% for high integration) than for negative affect (1.2% for high versus 0.8% for no negative affect). Most of the association between distress and drug/alcohol/suicide mortality appeared to result from confounding with structural factors and with pre-existing health conditions that may influence both the perception of distress and mortality risk. While deaths of despair result from self-destructive behavior, our results suggest that structural factors may be more important determinants than subjective distress.
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Genome integration technology has markedly expedited the construction of cell factories. However, its application is currently limited by the inefficient integration of large DNA fragments. Here, we report a CRISPR/Cas9 based integration of large DNA fragments (CILF) method to efficiently integrate large DNA fragments in Saccharomyces cerevisiae. In this approach, a fusion protein, Cas9-Brex27-FadR, was employed for the targeted delivery of donor plasmid to double-strand breaks (DSBs), while simultaneously recruiting Rad51 to enhance the efficiency of homologous recombination (HR). Our findings demonstrate that this method can achieve an integration efficiency of 98% for 10 kb DNA fragments and nearly 80% for 40 kb DNA fragments at a single site, using donor plasmids with 1000 bp homology arms (HAs) and 12 FadR binding sites (BSs). The CILF technique significantly enriches the synthetic biology toolbox of S. cerevisiae, offering significant potential to propel advancements in both synthetic biology and metabolic engineering.
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People can use their sense of hearing for discerning thermal properties, though they are for the most part unaware that they can do so. While people unequivocally claim that they cannot perceive the temperature of pouring water through the auditory properties of hearing it being poured, our research further strengthens the understanding that they can. This multimodal ability is implicitly acquired in humans, likely through perceptual learning over the lifetime of exposure to the differences in the physical attributes of pouring water. In this study, we explore people's perception of this intriguing cross modal correspondence, and investigate the psychophysical foundations of this complex ecological mapping by employing machine learning. Our results show that not only can the auditory properties of pouring water be classified by humans in practice, the physical characteristics underlying this phenomenon can also be classified by a pre-trained deep neural network.
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BACKGROUND: Leveraging electronic health record (EHR) data for clinical or research purposes heavily depends on data fitness. However, there is a lack of standardized frameworks to evaluate EHR data suitability, leading to inconsistent quality in data use projects (DUPs). This research focuses on the Medical Informatics for Research and Care in University Medicine (MIRACUM) Data Integration Centers (DICs) and examines empirical practices on assessing and automating the fitness-for-purpose of clinical data in German DIC settings. OBJECTIVE: The study aims (1) to capture and discuss how MIRACUM DICs evaluate and enhance the fitness-for-purpose of observational health care data and examine the alignment with existing recommendations and (2) to identify the requirements for designing and implementing a computer-assisted solution to evaluate EHR data fitness within MIRACUM DICs. METHODS: A qualitative approach was followed using an open-ended survey across DICs of 10 German university hospitals affiliated with MIRACUM. Data were analyzed using thematic analysis following an inductive qualitative method. RESULTS: All 10 MIRACUM DICs participated, with 17 participants revealing various approaches to assessing data fitness, including the 4-eyes principle and data consistency checks such as cross-system data value comparison. Common practices included a DUP-related feedback loop on data fitness and using self-designed dashboards for monitoring. Most experts had a computer science background and a master's degree, suggesting strong technological proficiency but potentially lacking clinical or statistical expertise. Nine key requirements for a computer-assisted solution were identified, including flexibility, understandability, extendibility, and practicability. Participants used heterogeneous data repositories for evaluating data quality criteria and practical strategies to communicate with research and clinical teams. CONCLUSIONS: The study identifies gaps between current practices in MIRACUM DICs and existing recommendations, offering insights into the complexities of assessing and reporting clinical data fitness. Additionally, a tripartite modular framework for fitness-for-purpose assessment was introduced to streamline the forthcoming implementation. It provides valuable input for developing and integrating an automated solution across multiple locations. This may include statistical comparisons to advanced machine learning algorithms for operationalizing frameworks such as the 3×3 data quality assessment framework. These findings provide foundational evidence for future design and implementation studies to enhance data quality assessments for specific DUPs in observational health care settings.
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Neurons in central nervous systems receive multiple synaptic inputs and transform them into a largely standardized output to their target cells-the action potential. A simplified model posits that synaptic signals are integrated by linear summation and passive propagation towards the axon initial segment, where the threshold for spike generation is either crossed or not. However, multiple lines of research during past decades have shown that signal integration in individual neurons is much more complex, with important functional consequences at the cellular, network, and behavioral-cognitive level. The interplay between concomitant excitatory and inhibitory postsynaptic potentials depends strongly on the relative timing and localization of the respective synapses. In addition, dendrites contain multiple voltage-dependent conductances, which allow scaling of postsynaptic potentials, non-linear input processing, and compartmentalization of signals. Together, these features enable a rich variety of single-neuron computations, including non-linear operations and synaptic plasticity. Hence, we have to revise over-simplified messages from textbooks and use simplified computational models like integrate-and-fire neurons with some caution. This concept article summarizes the most important mechanisms of dendritic integration and highlights some recent developments in the field.
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Despite converging evidence of hierarchical organization in the cerebral cortex, with sensory-motor and association regions at opposite ends, the mechanism of such hierarchical interactions remains elusive. This organization was primarily investigated regarding the spatiotemporal dynamics of intrinsic connectivity networks (ICNs). However, more effort is needed to investigate network dynamics in the frequency domain. We aimed to examine the integrative role of brain regions in the frequency domain with graph metrics. Phase-based connectivity estimation was performed in three frequency bands (0.011-0.038, 0.043-0.071, and 0.076-0.103 Hz) in the BOLD signal during rest. We applied modularity analysis to connectivity matrices and investigated those areas, which we called integrative regions, that showed frequency-domain flexibility. Integrative regions, mostly belonging to attention networks, were densely connected to higher-order cognitive ICNs in lower frequency bands but to sensory-motor ICNs in higher frequency bands. We compared the normalized participation coefficient (Pnorm) values of integrative and core regions with respect to their relation to higher-order cognition using a permutation-based t-test for multiple linear regression. Regression parameters of integrative regions in relation to three cognitive scores in executive functions, and working memory were significantly larger than those of core regions (Pfdr < 0.05) for salience ventral attention network. Parameters of integrative regions in relation to intelligence scores were significantly larger than those with core regions (Pfdr < 0.05) in dorsal attention network. Larger parameters of neuropsychological test scores in relation to these flexible parcels further indicate their essential role at an intermediate level in behavior. Results emphasize the importance of frequency-band analysis of brain networks.
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Understanding limiting factors of phenotypic plasticity is essential given its critical role in shaping biological adaptation and evolution in changing environments. It has been proposed that the pattern of phenotypic correlation could constrain trait plasticity. However, the interplay between phenotypic plasticity and integration has remained contentious. We experimentally simulated climate warming in juveniles of three subalpine tree species by exposing them to three-year in situ open-top chambers (OTCs), and then measured functional plasticity of 72 eco-physiological traits to evaluate whether phenotypic integration constituted an intrinsic constraint to plasticity. We also tested the relationship between the differences in plasticity and maintenance in trait integration. Phenotypic plasticity was positively associated with integration in deciduous tree species under warming. The difference in the plasticity of two paired traits could predict their integration in different environments, where traits displaying more similar plasticity were more likely to be correlated. Our study showed no indication that phenotypic integration constrained plasticity. More importantly, we demonstrated that differential plasticity between traits might result in a notable reorganization of the trait associations, and that warming commonly induced a tighter phenotype. Our study provides new insights into the interplay between phenotypic plasticity and integration in subalpine trees under climate warming.
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Supportive robotic solutions take over mundane, but essential tasks from human workforce in biomedical research and development laboratories. The newest technologies in collaborative and mobile robotics enable the utilization in the human-centered and low-structured environment. Their adaptability, however, is hindered by the additional complexity that they introduce. In our paper we aim to entangle the convoluted laboratory robot integration architectures. We begin by hierarchically decomposing the laboratory workflows, and mapping the activity representations to layers and components of the automation control architecture. We elaborate the framework in detail on the example of pick-and-place labware transportation - a crucial supportive step, which we identified as the number one area of interest among experts of the field. Our concept proposal serves as a reference architecture model, the key principles of which were used in reference implementations, and are in line with international standardization efforts.
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Sinusoidal amplitude modulation (SAM) is a key feature of complex sounds. While psychophysical studies have characterized SAM perception, and neurophysiological studies in anesthetized animals report a transformation from the cochlear nucleus' (CN; brainstem) temporal code to the inferior colliculus' (IC; midbrain's) rate code, none have used awake animals or nonhuman primates to compare CN and IC's coding strategies to modulation-frequency perception. To address this, we recorded single-unit responses and compared derived neurometric measures in the CN and IC to psychometric measures of modulation frequency (MF) discrimination in macaques. IC and CN neurons often exhibited tuned responses to SAM in rate and spike-timing measures of modulation coding. Neurometric thresholds spanned a large range (2-200 Hz DMF). The lowest 40% of IC thresholds were less than or equal to psychometric thresholds, regardless of which code was used, while CN thresholds were greater than psychometric thresholds. Discrimination at 10-20 Hz could be explained by indiscriminately pooling 30 units in either structure, while discrimination at higher MFs was best explained by more selective pooling. This suggests that pooled CN activity was sufficient for AM discrimination. Psychometric and neurometric thresholds decreased as stimulus duration increased, but IC and CN thresholds were higher and more variable than behavior at short durations. This slower subcortical temporal integration compared to behavior was consistent with a drift diffusion model which reproduced individual differences in performance and can constrain future neurophysiological studies of temporal integration. These measures provide an account of AM perception at the neurophysiological, computational, and behavioral levels.
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The literature widely supports the benefits of early integration of palliative care into pediatric oncological care; however, many barriers to its successful integration remain. Integrating palliative care as early as possible in the oncology pathway is critical, but other criteria are relevant to positive results. This paper aims to contribute to the early/late referral dualism in pediatric palliative care (PPC) and highlight the importance of a collaborative approach between oncologists and palliative care teams. This study investigates the impact of early versus late referral to PPC, intersecting it with the synergy work between services and the related outcomes. The four pediatric cancer cases were selected based on clinical (e.g., disease duration, multiple treatments, and pain management), management (e.g., involvement of multiple services and multiple home-hospital transitions), and relevance of multidisciplinary team (e.g., difficult clinical decisions and ethical discussions) criteria. A mixed-methods approach was employed, combining qualitative case analysis using clinical diaries, literature review, and practice guidelines development. Critical clinical information, time course, clinician-family communication, and patient involvement were analyzed. The outcomes show how simultaneous care creates continuous discussion and dialogue between professionals. The results indicate the importance of better communication and care coordination to improve patient and family satisfaction, highlighting the uniqueness of the pediatric field and the relationship with children and families. Through the discussion of clinical cases and a literature review, we provide practical guidance for clinicians working in oncology and PPC. These findings underscore the crucial need for a multidisciplinary approach in pediatric oncology, advocating policy changes to support early PPC integration and translate it into complementarity best operating practices. In conclusion, besides assessing the timeliness of referral to the PPC service, the synergy, harmony, and choral work of the professionals involved are equally valuable for a quality-of-life-oriented care plan.
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Our mental representation of our body depends on integrating various sensory modalities, such as tactile information. In tactile distance estimation (TDE) tasks, participants must estimate the distance between two tactile tips applied to their skin. This measure of tactile perception has been linked to body representation assessments. Studies in individuals with fibromyalgia (FM), a chronic widespread pain syndrome, suggest the presence of body representation distortions and tactile alterations, but TDE has never been examined in this population. Twenty participants with FM and 24 pain-free controls performed a TDE task on three Body regions (upper limb, trunk, lower limb), in which they manually estimated the interstimuli distance on a tablet. TDE error, the absolute difference between the estimation and the interstimuli distance, was not different between the Groups, on any Body region. Drawings of their body as they felt it revealed clear and frequent distortions of body representation in the group with FM, compared to negligible perturbations in controls. This contrast between distorted body drawings and unaltered TDE suggests a preserved integration of tactile information but an altered integration of this information with other sensory modalities to generate a precise and accurate body representation. Future research should investigate the relative contribution of each sensory information and prior knowledge about the body in body representation in individuals with FM to shed light on the observed distortions.
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BACKGROUND: Information about the development of cognitive skills and the effect of sensory integration in children using auditory brainstem implants (ABIs) is still limited. OBJECTIVE: This study primarily aims to investigate the relationship between sensory processing skills and attention and memory abilities in children with ABI, and secondarily aims to examine the effects of implant duration on sensory processing and cognitive skills in these children. METHODS: The study included 25 children between the ages of 6 and 10 years (mean age: 14 girls and 11 boys) with inner ear and/or auditory nerve anomalies using auditory brainstem implants. Visual-Aural Digit Span Test B, Marking Test, Dunn Sensory Profile Questionnaire were applied to all children. RESULTS: The sensory processing skills of children are statistically significant and positive, and moderately related to their cognitive skills. As the duration of implant use increases, better attention and memory performances have been observed (p < .05). CONCLUSION: The study demonstrated the positive impact of sensory processing on the development of memory and attention skills in children with ABI. It will contribute to evaluating the effectiveness of attention, memory, and sensory integration skills, and aiding in the development of more effective educational strategies for these children.