Background: Despite the potential benefits, the effects of Hybrid Assistive Limb (HAL) gait training on changes in neuromuscular activation that accompany functional gains in individuals with spinal muscular atrophy (SMA) type III is not well known. In this article, we quantify the effects of HAL gait training on spatial muscle activity patterns in a patient with SMA type III using multi-channel surface electromyography (SEMG).Methods: A 21-years old male  with spinal muscular atrophy type III, when diagnosed at 18-years old by genetic screening, participated in this case study. Although he presented with forearm distal muscle weakness, atrophy of the intrinsic muscles of the hand, and neuromuscular fatigue, his activities of daily living is independent. The patient underwent a separate, single 33-minute session of both HAL and treadmill gait training. To evaluate the coefficient of variation (CoV) of force and alterations in the SEMG spatial distribution patterns, modified entropy and CoV of root mean square (RMS) were calculated from the vastus lateralis (VL) muscle before and after the intervention of HAL and treadmill gait training. Each training session was separated by a period of one month to avoid cross-over effects.Results: There was a greater decrease in the ΔCoV of force and an increase in the magnitude of whole VL muscle activation from pre-intervention to post-intervention with the HAL gait training as compared to the treadmill gait training. In response to only HAL gait training, the CoV of RMS was higher, and the modified entropy was lower post-intervention than pre-intervention.Conclusions: Our results support the notion that HAL gait training has a positive benefit on motor output not only in the magnitude of SEMG generated but also the patterns of neural activation. In particular, the Hybrid Assistive Limb (HAL) gait training has resulted in improved gait and balance performance. The HAL exoskeleton is completely driven by the patient’s own muscle activation, which is detected by surface electrodes on key lower extremity muscle groups. Thus, this self-initiated robotic-assisted movement has the potential to induce a somatosensory feedback-loop that enhances neural plasticity and locomotor function. Although many previous studies have reported functional gains due to the HAL intervention , there are no studies that report its effects on neuromuscular activation likely to accompany functional gains. Understanding how HAL training changes neuromuscular activation patterns, will help in the evaluation and use of HAL training across various populations.Several clinical trials of robot-assisted gait training have been reported in neurology patients. This technique provides data on the spatial distribution of SEMG within a muscle. Previous studies have demonstrated that the spatial distribution of SEMG is altered by contraction levels or fatigue during isometric contraction. This phenomenon has been explained by a spatial inhomogeneity in the location of different types of muscle fibers and a clustering of muscle fibers innervated by one motor unit in a limited territory. Previous studies have demonstrated that alterations in the multi-channel SEMG spatial distribution pattern can be explained by the physiological phenomenon of motor unit recruitment and suggested that the multi-channel SEMG spatial distribution pattern could be used to study changes in motor unit recruitment patterns. In addition, previous studies have used metrices such as the inhomogeneity of the spatial distribution pattern of SEMG  of root mean square (RMS) to quantify neuromuscular fatigue and the influence of force generation. The assessment of motor unit recruitment is very important for determining the effect of neurorehabilitation on neuroplasticity in patients with several types of neurological conditions. Thus, we considered that this technique  could be employed as a new assessment tool to evaluate changes in muscle activation as a metric of neuroplasticity in response to HAL training.Multi-channel surface electromyography (SEMG) is a recently developed techniques used to evaluate single motor unit firing behavior and whole muscle EMG patterns of activity by using multiple electrodes arranged in a two-dimensional plane. Rehabilitation is one treatment for SMA type III. The main objectives for rehabilitation of individuals with SMA type III who are still able to walk are to maintain, restore or promote function, mobility, and adequate joint range, and improve balance and endurance. HAL gait training has been an insurance supported therapy since January 2016, and SMA, amyotrophic lateral sclerosis, spinal bulbar atrophy, Charcot-Marie-Tooth disease, inclusion body myositis, distal myopathy, and congenital myopathy are targeted disease populations. Although approved by insurance, there is limited information on how the effectiveness of HAL training compares to other forms of therapy. Specifically, there is no report which compares HAL and conventional treadmill gait training on neuromuscular activation in SMA patients that likely accompany improvements in walking function. Therefore, the aim of this case report to quantify the effects of a single session of HAL gait training on SEMG spatial distribution patterns in a person with spinal muscular atrophy type III. We hypothesized that HAL gait training would induce more heterogenous muscle activation reflecting more varied motor unit recruitment than treadmill gait training.Individuals with spinal muscular atrophy (SMA) type III present with progressive proximal weakness of the legs more than arms, and the leg weakness is so profound that it can necessitate the long term need of a wheelchair for mobility. The participants’ knee extension strength  and 6MWT (567 m) were lower than the above value, and we have chosen the weaker leg to measure EMS recording.A 21-year-old male  with spinal muscular atrophy type III when diagnosed at 18-years old by genetic screening participated in this study. Written informed consent was obtained from the patient to perform the two types of gait training and to publish the obtained his anonymized data to be published in this article. All procedures were performed in accordance with the Declaration of Helsinki and were approved by the Hiroshima University’s Committee on Ethics in Research . He presented with forearm distal muscle weakness, atrophy of the intrinsic muscles of the hand, and neuromuscular fatigue. The patient’s baseline physical performance data are shown in The peak MVC torque was used as the maximal effort and to calculate the target torque for the isometric sub-maximal ramp-up contractions. After MVC measurements, the participant performed an isometric submaximal ramp-up contraction of the knee extensors in the weaker leg one time from 0% to 80% of the MVC force with an increase rate of approximately 10% of the MVC per sec. The participant-generated torque and target torque were displayed on a computer monitor. Prior to motor testing, the participant practiced the MVC and sub-maximal ramp-up contraction at least 10 min before the motor testing session began. The CoV of force (standard deviation (SD)/mean x 100, CV force) was calculated from the ramp up contraction task.The participant performed maximal isometric voluntary contractions (MVC) of the knee extensors bilaterally at the pre- and post-intervention. Isometric knee extension was performed using a Biodex system . During contractions, both the hip and knee extension angles were positioned at 90 degrees. The MVC involved a gradual increase in knee extension torque from 0 Nm to his maximum torque over three seconds, with the maximum torque being held for two seconds. The participant performed at least two MVC trials with > 120 s of rest between trials and a warm-up for 10 min, including indoor walking and lower limb stretching before the MVC measurement. The grid consisted of 13 columns and five rows of electrodes , with one missing electrode in the upper left corner. The participant’s thigh hair was removed, and the skin was cleaned with alcohol. The electrode was attached to the skin with a bi-adhesive sheet  after a conductive paste  was applied. The center of the electrode grid was positioned at the center of the line between the superior lateral edge of the patella and the greater trochanter protuberance. The columns of the electrode grid were placed parallel to the longitudinal axis of the VL muscle. A reference electrode was attached at the anterior superior iliac spine. All procedures were performed by the same investigator.During the sub-maximal contraction, multi-channel SEMG signals were detected from the weaker side of vastus lateralis (VL) muscle using a semi-disposable grid of 64 electrodes  according to the same procedures used in previous studies. Since the selected ramp rate was 10% of the MVC force per second, one epoch of the sampled signal was overlapped by 0.5 seconds between neighboring torque levels. We normalized the RMS estimates to the values obtained pre-intervention for each torque level.Monopolar multi-channel surface EMG signals (64 channels) were amplified by a factor of 1000, sampled at 2048 Hz, and digitized by a 12-bit analog-to-digital converter . The recorded monopolar signals were off-line bandpass filtered (10-500 Hz) and transferred to analysis software . Bipolar multi-channel SEMG signals (n = 59) along the columns were obtained from the 64 electrodes. The EMG signals were divided in epochs of one second centered at each 10% of MVC force increment from 10% to 80% of the MVC ramp-contraction to calculate the root mean square (RMS).To characterize the heterogeneity in the multi-channel SEMG spatial distribution pattern at each epoch, we determined the modified entropy and correlation coefficients. The modified entropy of the spatial distribution of the ΔSEMG amplitude was calculated over a 1-s epoch taken at 10% to 80% of the MVC during the ramp-up contraction. According to methods published by Farina et al., modified entropy was defined as the entropy of the signal power as follows:p(i) is the square of the RMS value of channeli divided by the sum of the squares of all 59 RMS values at the given contraction level. Therefore,p(i)2 represents the normalized power of each channel. Modified entropy is the normalized power of the EMG signal across the array and reflects the heterogeneity in the muscle activity. The CoV of the RMS was defined as the quotient of the SD of the Δ59 RMS measurements and the average of Δ59 RMS measurements at each given torque level. Both a decrease in modified entropy and an increase in CoV of RMS indicate increased heterogeneity in the multi-channel SEMG spatial distribution pattern within the electrode grid. Measures of the CoV of the RMS and modified entropy provide insight into how the nervous system regulates muscle activation across the muscle irrespective of the magnitude.whereThe patient performed two types of gait training separated by a period of one month between training to avoid training effect.HAL gait trainingThe patient performed gait training using the HAL for 33 minutes (gait distance about 2200 m). The double leg type HAL was used for gait training, which was performed with two physical therapists for the operation of the HAL commands and support of the patient. During HAL gait training, a walking hoist  was used to prevent falls and adjust the patient’s posture.Treadmill gait trainingThe patient performed gait training using the treadmill for 33 minutes . During gait training, Alter-G  was used to prevent falls and adjust the patient’s posture without providing weight bearing and clinician’s support to leg movements.As a neuromuscular activation assessment, multi-channel SEMG was performed on the patient before and after both gait training.We applied multichannel SEMG as a neuromuscular activation assessment of HAL training. In addition to the overall increase in EMG activity, the HAL gait training resulted in decrease force fluctuation, and greater heterogeneity in spatial muscle distribution pattern from pre-intervention to post-intervention than for the treadmill gait training. The SEMG spatial distribution pattern can be altered by contraction levels or fatigue during isometric contraction. Measures of the CoV of the RMS and modified entropy provide insight into how the nervous system regulates muscle activation across the muscle irrespective of the magnitude. This phenomenon has been explained by spatial heterogeneity in the location of different types of muscle fibers and a clustering of muscle fibers innervated by one motor unit in a limited territory, and a previous study reported that alterations in the multi-channel SEMG spatial distribution pattern can be explained by the physiological phenomenon of motor unit recruitment patterns. The results of the present report for the HAL training intervention showed that the CoV of the RMS was higher, and the modified entropy was lower than for treadmill gait training. These findings suggest that spatial motor unit activity patterns were enhanced by HAL training. Changes in the heterogeneity of SEMG were accompanied by a greater decreased in the Δ CoV force for the HAL gait training as compared to the treadmill gait training. This finding suggests that the participant was able to perform the submaximal ramp up task smoothly by altered spatial motor unit activity patterns.We used two parameters to quantify the multi-channel SEMG spatial distribution pattern: modified entropy and the CoV of the RMS. A decrease in the modified entropy and an increase in the CoV of the RMS are consistent with increased heterogeneity in the multi-channel SEMG spatial distribution pattern within the electrode grid. The voluntary drive and normalized motion assistance provided by the external device likely form the foundation for a proprioceptive feedback loop for patients with lesions involving the sensory pathway and not facilitated as well with treadmill training. The neural activity and repeated execution of specific tasks promote learning and lead to the reinstatement or restructuring of appropriate proprioceptive feedback. Here, we are the first to show that HAL gait training induced an alteration muscle activation patterns due to a single session of HAL training. Moreover, based on our findings, HAL gait training may be more effective in evoking changes in neuromuscular activation than conventional gait training. Future studies will examine the relationship between changes in gait and muscle activation using the HAL intervention across multiple sessions.The HAL gait training offers the possibility to monitor muscle contractions via SEMG at the extensor and flexor muscle region of the lower extremities.This report has several limitations. First, report included only one patient with spinal muscular atrophy type III. Future large-sample studies and studies of patients with various neurological conditions  are needed to clearly understand how generalizable the effects of HAL gait training on neuroplasticity. Second, this report only included data following a single session. Future studies will examine how factors such as dose, frequency, and intensity of HAL training affect changes in function and neuromuscular activation.The present case report showed that HAL gait training was more effective in changing metrics of neuromuscular activation of the knee extensors than treadmill gait training despite similar training durations. These data suggest that the modes of gait training which incorporate both voluntary activation and guided movement of the legs may facilitate recovery of function.Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.https://doi.org/10.6084/m9.figshare.14113178.v1.Figshare: EMG data of VL muscle,Creative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the The manuscript describes the multichannel EMG analysis of the limb muscle of a patient with muscle atrophy. The patient performed ramp contractions and EMG maps were analyzed computing entropy. The methods are described accurately and the technology used is solid as well as the equipment used. The results are interesting, well commented and well described. The present reviewer has no additional request for changes.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Electromyography, biomechanics, rehabilitationI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The objective of this study was to quantify the effects of HAL gait training on spatial muscle activity patterns in a patient with SMA type III using multi-channel surface electromyography (SEMG). The authors support in conclusion the notion that HAL gait training has a positive benefit on motor output not only in the magnitude of SEMG generated but also the patterns of neural activation. The approach of the study appears very original and the contents of the manuscript are quite interesting by his methodology and through the tools of quantification used.All procedures were performed in accordance with the Declaration of Helsinki and were approved by the Hiroshima University’s Committee on Ethics in Research . Our institution does not require ethical approval for reporting individual cases or case series”. The details are not clear and must be re writting. For instance "Our institution does not require ethical approval for reporting individual cases or case series” what I recommend to the authors to delete. The manuscript reads smoothly and is easy to understand. The aims, scope, and results of the study are clearly stated. I have very much enjoyed reading this paper. I find it interesting and clearly written, and satisfying also all the other publication criteria of the “F1000Research”. The study provides a very valuable addition to this line of research, and adds relevantly to the subject with additional original findings. I thus find that this paper definitively delivers results that will surely be of interest to the readership of the “F1000Research”. I recommend the publication of this interesting paper after more details concerning the Ethical Committee “Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:biomechanics, health disease and rehabilitationI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Dear Prof. Redha Taiar, Thank you for reviewing this paper and helpful comments. We have removed the bellow sentence.Our institution does not require ethical approval for reporting individual cases or case series” "


Dentigerous cysts (DC) are the most common odontogenic cystic lesions of inflammatory origin occurring in children. These lesions can be treated by enucleation with or without related impacted teeth or marsupialization/decompression. The latter procedures have been used successfully for many years, but decompression is increasingly recommended in children because of its good outcomes and the preservation of the developing tooth. This conservative surgical technic allows simultaneously the normal eruption of the involved permanent teeth and the ossification of the bony defect. The present report describes an 8-year-old female patient with an inflammatory DC associated with an endodontically treated primary molar accidentally discovered on panoramic radiograph. Decompression of the cyst was performed, by means of a removable space maintainer acting as an acrylic obturator after removal of teeth 83 and 84. Ten months after the decompression procedure, a complete resolution and regression of the cystic lesion with full spontaneous eruption of the premolar were observed. From the age of 5 to 12 years, children are in mixed dentition. At this age, to ensure proper eruption of the permanent dentition and to prevent arch length deficit and loss of space, it is important to preserve the primary teeth [Several disturbances can cause either infection or necrosis of the pulp tissue of primary teeth, and since pulp therapy is not always easy to perform on these teeth because of their complex anatomy, the preservation of primary teeth can induce undesirable effects on the permanent successor, such as the formation of inflammatory DC .These cysts are caused by the accumulation of fluid between the reduced enamel epithelium and the crown of the tooth . AlthougEnucleation with or without impacted teeth or marsupialization/decompression are the treatments of choice of inflammatory DC. Both procedures, marsupialization and decompression, have been used successfully for many years, but decompression is increasingly recommended because of its successful outcomes and preservation of the developing tooth structure .Since these cysts are more common in children, conservative management by decompression may be recommended, allowing the conservation of the permanent involved tooth , 8.The present report is aimed at describing a complete regression of an inflammatory DC with full spontaneous eruption of the premolar ten months after a decompression procedure in an 8-year-old female patient.The present clinical case report was reported according to the CARE (CAse REport) Guidelines .An eight-year-old female patient consulted the Department of Pediatric and Preventive Dentistry at the Faculty of Dental Medicine of Monastir for dental malocclusion management.Written informed consent was obtained from the child's parents for all imaging exams, treatment modalities, and data publications.The panoramic radiograph performed for the interceptive orthodontic treatment revealed a large unilocular radiolucency repressing the dental germ of the first lower-right premolar (#44) including the lower-right deciduous canine (#83), and associated with a treated root of nonvital lower-right first primary molar (#84) .The medical history of the patient did not reveal any specific systematic diseases or previous traumatic injuries in the affected area.The extraoral examination seemed to show no abnormalities while the intraoral examination revealed an imperceptible expansion of the buccal cortical on the alveolar ridge in relation to teeth 83 and 84.Inspection showed a normal looking mucosa . PalpatiA retroalveolar radiograph was performed and showed a well-defined surrounded by a slight peripherical radiopaque thickening lesion apical to the lower-right first primary molar (#84) .To confirm the lesion limits, a cone-beam computed tomography (CBCT) was requested.The sagittal and coronal views of the CBCT revealed a 12 mm diameter well-demarcated unilocular radiolucency Figures  and 5.The lesion was identified in the mandibular right region causing expansion of the buccal cortical with no signs of root resorption in the adjacent tooth and surrounding the crown of the unerupted first premolar (tooth 44).The first lower-right premolar germ was forced against the lingual cortical with a mesial angulation. Based on the above-mentioned clinical and radiological findings, a provisional diagnosis of inflammatory DC was made.The second primary molar and canine were extracted under local anesthesia, and a conservative approach by decompression to preserve the mandibular first premolar was followed.The extraction socket was extended to establish a communication between the cyst and the oral cavities without disturbing the erupting premolar .The cystic fluid was evacuated under irrigation with normal saline solution through the socket.An iodoform gauze was then packet into the lesion cavity, and sutures were placed.The patient and her parents were advised to follow postsurgical instructions, rinsing the opening cyst twice a day with saline solution.For the first 48 hours, postoperative care included the use of a cold pack. For pain management, 200 mg dexibuprofen three times a day was prescribed for the young patient.Two days postoperatively, an impression was made before gently removing the gauze which helped to prevent the alginate from getting the bone cavity. Then, a removable space maintainer acting as an acrylic obturator was designed .During the surgical procedure, a tissue sample was taken for biopsy. Microscopically, the cyst was lined with cuboidal nonkeratinized stratified epithelium resembling reduced enamel epithelium, and the underlying connective tissue capsule showed chronic inflammatory cell infiltration. The histopathological examination confirmed the initial diagnosis of the inflammatory DC.The acrylic obturator remained until the eruption of tooth 44 was visualized using a subsequent radiographic evaluation.The follow-up appointments were scheduled every three months postsurgery.The three-month postoperative radiograph showed a reduction in radiolucency associated with a gradual spontaneous eruption of the tooth .After 10 months follow-up, the radiographic and clinical findings showed that the affected teeth successfully erupted without any intervention.The tooth was vital with almost a complete root formation Figures  and 10.According to the World Health Organization (WHO) classification of odontogenic lesions, odontogenic cysts were divided into developmental and inflammatory cysts. The inflammatory odontogenic cysts included radicular cysts and inflammatory collateral cysts while the developmental odontogenic and nonodontogenic cysts included dentigerous cysts, lateral periodontal cysts, botryoid odontogenic cysts, gingival cysts, glandular odontogenic cysts, orthokeratinized odontogenic cysts, and nasopalatine duct cysts .The DCs constitute the most frequent maxillary cystic lesions (30% of the odontogenic cysts) , with soThese cysts are also very common in mixed dentition and are usually associated with the roots of a nonvital or necrotic primary tooth and the crown of an unerupted permanent tooth , such deThe pathogenesis of DC is still controversial. However, three possible mechanisms were proposed in the literature .The first mechanism suggested that the developmental DC might form a dental follicle and might become inflamed later . The secThe follicle of permanent successor might get secondarily infected from either periapical inflammation of a nonvital primary tooth or other source leading to a DC formation, and this inflammatory process may explain the DC development in the present report .For this reason, especially in mixed dentition, it is very important to establish not only a clinical but also a radiological follow-up of the endodontically treated primary molars until the eruption of permanent successors to be able to detect as soon as possible the side effects of pulp therapy and to manage them in prompt time.Usually, DCs are asymptomatic and are discovered during routine dental radiographies .Radiographically, these developmental cysts are characterized by the presence of a radiolucent, well-defined, unilocular lesion around the crown of an unerupted permanent tooth. They can be reported in the presence of exformation of the maxillaries, dental structures shifting, or delays in dental eruptions . In the According to the literature, the DC management is exclusively surgical, and two treatment techniques have been suggested: the enucleation or the marsupialization/decompression.In their retrospective study, Iatrou et al. choose the technique of enucleation, reserving the marsupialization to large cysts. An association of both techniques can be suggested for the more aggressive cysts to reduce the volume of the lesion, before surgical removal .Conservative techniques for the treatment of odontogenic cysts have evolved gradually the last decades.Marsupialization and decompression are minimal surgical intervention but decompression is less invasive because it requires a smaller bony window.Decompression may envelop marsupialization, and it includes any method that keeps an opening into the exterior by using a conduit to decrease intracystic pressure .The benefits of decompression are maintenance of pulp vitality, prevention of maxillary fractures, preservation of the inferior alveolar nerve or maxillary sinus, and low risk of recurrence .In the present reported case, since the patient and her parents were cooperative, the decompression was recommended.After decompression, the cystic cavity must remain open; numerous means have been described such as stents, stents fixed by mini-screws, packs of iodoform gauze, tubes for decompression, and retainers .Ghandour et al. recommended the placement of a gauze during the first two days after the surgery to keep the surgical site open . PreservIn mixed dentition, a loss of space may occur during the first three weeks following the extraction of the primary teeth; for this reason, maintaining the space is necessary to avoid the decrease in the arch length . In the A clinical and radiographic follow-up will be necessary, every three months initially, then every six months, until the end of the eruption of the tooth and the healing of the bone .Both radiological and clinical findings after 10 months showed in the present report that the first premolar had successfully erupted without any orthodontic intervention.Although the predictive criteria for this eruption remain unknown, the size of the cystic lesion does not constitute a risk factor for the eruption.In fact, the most favorable predictive factors are essentially the age of the patient (less than ten years old), the depth of the inclusion (less is better), and the angulation of the germ (inferior to 25°) .After minimal surgical intervention, the spontaneous eruption may occur in approximately 70% to 90 of cases. The length of the eruption is very variable, ranging from seven months to five years, and orthodontic traction can be associated , 21.Extraction of the primary infected tooth and decompression is the treatment of choice for infected dentigerous cyst in mixed dentition.The surgical procedure can be followed by wearing of an acrylic resin obturator, incorporating features of space maintainer especially when primary molars are involved, both to maintain the surgical opening during healing and to prevent the arch length deficiency.This report highlights the interest of performing a systematic radiological examination during the child's first visit.


The effectiveness of trust has been extensively investigated in entrepreneurship studies. However, compared to the outcomes of trust, we still lack knowledge about the mechanisms underlying venture capitalists' initial trust in entrepreneurs. Drawing from signal theory and impression management theory, this study explores an impression management motivational explanation for the influencing factors of venture capitalists' initial trust. An empirical test is based on 202 valid questionnaires from venture capitalists, and the results indicate that the signal of five dimensions of entrepreneurial orientation has a significant impact on the initial trust of venture capitalists and that a signal of entrepreneurial orientation of perseverance or passion positively influences venture capitalists' initial trust through acquired impression management strategies, while a signal of entrepreneurial orientation of risk-taking, innovation, or proactivity positively affects the initial trust of venture capitalists through defensive impression management strategies. The perceptions of entrepreneurs' hypocrisy by venture capitalists negatively moderate the relationship between acquired impression management strategies and the initial trust of venture capitalists and negatively moderate the relationship between defensive impression management strategies and the initial trust of venture capitalists. During the economic transition period, the business environment is changing rapidly. How to obtain external resources to promote corporate growth for “new and weak” start-ups has gradually become an urgent problem to be solved in academic and practical circles. The trust of venture capitalists in entrepreneurs, as one of the important ways for start-ups to obtain external “soft” resources, affects the success or failure of start-ups to a large extent. Studies have confirmed that the trust of venture capitalists in entrepreneurs helps entrepreneurs to obtain financial capital and strategic advice for new ventures, thereby enhancing the level of innovation : The signal of entrepreneurs' perseverance orientation is positively related to venture capitalists' initial trust.Hypothesis 1b (H1b): The signal of entrepreneurs' passion orientation is positively related to venture capitalists' initial trust.Hypothesis 1c (H1c): The signal of entrepreneurs' risk-taking orientation is positively related to venture capitalists' initial trust.Hypothesis 1d (H1d): The signal of entrepreneurs' innovation orientation is positively related to venture capitalists' initial trust.Hypothesis 1e (H1e): The signal of entrepreneurs' proactivity orientation is positively related to venture capitalists' initial trust.According to the content of the signal, it can be divided into quality signals and intention signals. Quality signals convert invisible capabilities into externally observable signals, while intention signals indicate the direction of organizational behavior. That is, in addition to different entrepreneurial orientations that have a direct impact on the initial trust of venture capitalists, entrepreneurs can also intentionally release signals to the outside world to influence venture capitalists' perceptions of their abilities and judgment, so that they can then consider whether to give trust. How do entrepreneurs release signals through which their entrepreneurial orientation can affect the initial trust of venture capitalists? From the perspective of social psychology, individuals not only pay close attention to how others view and evaluate them but also change their behavior based on others' views : The acquired impression management strategy plays a mediating role between entrepreneurs' perseverance orientation and venture capitalists' initial trust.Hypothesis 2b (H2b): The acquired impression management strategy plays a mediating role between entrepreneurs' passion orientation and venture capitalists' initial trust.Hypothesis 2c (H2c): The defensive impression management strategy plays a mediating role between entrepreneurs' risk-taking orientation and venture capitalists' initial trust.Hypothesis 2d (H2d): The defensive impression management strategy plays a mediating role between entrepreneurs' innovation orientation and venture capitalists' initial trust.Hypothesis 2e (H2e): The defensive impression management strategy plays a mediating role between entrepreneurs' proactivity orientation and venture capitalists' initial trust.Perceptions of hypocrisy refer to the individual's perception of the inconsistency between the words and deeds of others : Perceptions of hypocrisy negatively moderate the relationship between the acquired impression management strategy and venture capitalists' initial trust.Hypothesis 3a (H3a): Perceptions of hypocrisy negatively moderate the relationship between the defensive impression management strategy and venture capitalists' initial trust.Based on the above theoretical view and research hypotheses, the theoretical model of this research is shown in Taking into account the research on venture capitalists' initial trust in entrepreneurs before the cooperative relationship, according to the definition of new ventures by McDougall and Robinson , ventureThe measurement scales used in this study are all scales with good reliability and validity in the Chinese and English literature, and they were ultimately determined after back-translation procedures. Except for controlled variables, all variables were scored with a five-point Likert scale ranging from 1  to 7 . The measurement of the independent variable entrepreneurial orientation was based on the scale developed by Santos et al.  with fivThe sample data were collected by questionnaire in our study, and the measurement items were answered by the venture capitalists themselves, which may incur the problem of common method bias. To ensure the reliability of the research results, we used SPSS 21.0 for Harman's single-factor test and carried out principal component analysis (PCA) on all measurement items of the core variables involved in the research. The data results show that among the seven principal components extracted by the unrotated component matrix, there is no single component that can explain the overall variation, and the first principal component with the largest eigenvalue explains the variation of 26.48%, less than half the overall variation of 70.22%, which shows that there is no serious common method bias in our study.We conducted confirmatory factory analyses (CFAs) to test the discriminant validity of the research variables included in our study: perseverance orientation, passion orientation, risk-taking orientation, innovation orientation, proactivity orientation, acquired impression management strategies, defensive impression management strategies, perceptions of hypocrisy, and initial trust. As shown in According to the steps proposed by MacKinnon , we used0.324, p < 0.001) and passion orientation  have significant positive effects on the initial trust of venture capitalists. Therefore, H1a and H1b are further supported. The second step is to examine the direct influence of perseverance orientation and passion orientation on acquired impression management strategies. M3 and M4 in 0.340, p < 0.001). Passion orientation has a significant positive impact on acquired impression management strategies . The third step is to examine the relationship between the acquired impression management strategies and the initial trust of venture capitalists. M5 and M6 indicate that when perseverance orientation and passion orientation are controlled respectively, there is a significant regression relationship between acquired impression management strategies and the initial trust of venture capitalists . In addition, the bootstrap method based on the percentile deviations shows that the mediating effect between perseverance orientation and the initial trust of venture capitalists is significant , and the mediating effect accounts for 11.8% of the total effect; in addition, the mediating effect between passion orientation and the initial trust of venture capitalists is significant , and the mediating effect accounts for 9.6% of the total effect. Therefore, H2a and H2b are supported.Regarding the mediating effect of acquired impression management strategies, the specific results are shown in 0.442, p < 0.001), innovation orientation , and proactivity orientation  have significant positive effects on the initial trust of venture capitalists. Therefore, H1c, H1d, and H1e are further supported. The second step is to examine the direct influence of risk-taking orientation, innovation orientation, and proactivity orientation on acquired impression management strategies. M10, M11, and M12 in 0.217, p < 0.001), innovation orientation , and proactivity orientation  have a significant positive impact on defensive impression management strategies. The third step is to examine the relationship between defensive impression management strategies and the initial trust of venture capitalists. M13, M14, and M15 indicate that when risk-taking orientation, innovation orientation, and proactivity orientation are controlled, there is a significant regression relationship between defensive impression management strategies and the initial trust of venture capitalists . In addition, the bootstrap method based on the percentile deviations shows that the mediating effect between risk-taking orientation and the initial trust of venture capitalists is significant , and the mediating effect accounts for 20.9% of the total effect; the mediating effect between innovation orientation and the initial trust of venture capitalists is significant , and the mediating effect accounts for 30.7% of the total effect; and the mediating effect between proactivity orientation and the initial trust of venture capitalists is significant , and the mediating effect accounts for 31.3% of the total effect. Therefore, H2c, H2d, and H2e are further supported.Regarding the mediating effect of defensive impression management strategies, the analysis results are shown in 0.182, p < 0.001), and this main effect is moderated by the perception of hypocrisy , indicating that the perception of hypocrisy negatively moderates the relationship between acquired impression management and the initial trust of venture capitalists. Similarly, M17 shows that there is a main effect between defensive impression management strategies and the initial trust of venture capitalists , and this main effect is moderated by the perception of hypocrisy , indicating that the perception of hypocrisy negatively moderates the relationship between defensive impression management and the initial trust of venture capitalists. Therefore, H3a and H3b are supported.This study refers to model 4 in the SPSS PROCESS program developed by Hayes  to test 0.343, t = 4.239, p < 0.001), while when the perception of hypocrisy (M+SD) is high, the entrepreneur's use of acquired impression management strategies no longer has a significant effect on the initial trust of venture capitalists , which further supports H3a. 0.693, t = 8.014, p < 0.001). When the perception of hypocrisy (M+SD) is high, although the entrepreneur's defensive impression management strategies also have a positive effect on the initial trust of venture capitalists, the effect is small . This shows that with the gradual increase in the perception of hypocrisy, the impact of entrepreneurs' defensive impression management strategies on the initial trust of venture capitalists gradually decreases. H3b is therefore verified.To further test whether the moderating effect of perception of hypocrisy is in line with the presupposed expectation, this study follows the methods proposed by Aiken and West  to conduThere are three main conclusions in our study. Firstly, entrepreneurial-oriented signals have a positive impact on the initial trust of venture capitalists. This conclusion is consistent with our expected hypothesis, which shows that entrepreneurs can gain the initial trust of venture capitalists by releasing entrepreneurial-oriented signals. Previous studies have shown that entrepreneurs can convey their potential qualities and abilities to venture capitalists through information signals at the stage of entrepreneurial presentation (Eddleston et al., Second, entrepreneurs' impression management strategy plays a part of mediating role between entrepreneurial orientation and initial trust of VC. This conclusion is roughly consistent with the conclusion of Tang et al. . They foThird, perception of hypocrisy negatively moderates the relationship between impression management strategies and the initial trust of VC. Specifically, the lower the VC's perception of hypocrisy on the entrepreneur, the stronger the positive impact of the entrepreneur's acquired impression management strategy and defensive impression management strategy on the initial trust of the venture capitalist, and vice versa. This indicates that when entrepreneurs convey different entrepreneurial orientation signals to venture capitalists through different impression management strategies, they should not only take into account the need to actively show themselves to venture capitalists but also reduce the concerns of venture capitalists about their own integrity and ability. Otherwise, once the venture capitalist perceives the entrepreneur to be hypocritical, his or her initial trust will be greatly reduced. As founded by Chen and Ye , behavioThe theoretical contributions of this paper are shown in the following three main aspects. First, our study links the entrepreneurial orientation with the initial trust of venture capitalists and expands the research about the antecedent variable of the initial trust of venture capitalists. Previous studies have theoretically emphasized that the initial trust of venture capitalists on entrepreneurs before cooperation is characterized by competence, goodwill, and integrity and pointed out that this trust helps to promote the initial investment of venture capitalists, thus affecting mutual trust after investment (Wang and Dong, Second, we propose and test the mediating role of impression management strategies between entrepreneurial orientation and initial trust and refine the legitimacy of impression management. Previous studies have mostly explained the construction of trust between venture capitalists and entrepreneurs based on the perspectives of resource conservation theory, social exchange theory, and social relationship networks, while there are relatively few studies from the perspective of impression management strategy theory. In the existing research on the role of impression management, most of the research has discussed the effects of impression management, such as how entrepreneurs use impression management to gain or maintain legitimacy, especially to resist stigma and obtain entrepreneurial well-being after failure. However, few scholars have paid attention to entrepreneurs' impression management strategies and venture capitalists' initial trust before the establishment of entrepreneurial partnerships. This study discusses and confirms that the initial trust of entrepreneurial orientation to venture capitalists is mediated by the entrepreneur's impression management strategy. The introduction of the impression management strategy not only reveals the psychological mechanism of entrepreneurial orientation as a signal to the initial trust of venture capitalists but also breaks through the phenomenon that the previous literature mainly uses resource preservation and social exchange as the formation mechanism of trust.Third, this study explains under what conditions different impression management strategies affect the initial trust of venture capitalists. Although entrepreneurs can transmit different entrepreneurial orientation signals to venture capitalists by using impression management strategies, and they will get the initial trust of venture capitalists, but venture capitalists will not blindly trust them, which means that whether different impression management strategies can ultimately transform the initial trust of venture capitalists depends on the cognitive evaluation of venture capitalists. Previous studies have confirmed that when venture capitalists make investment decisions, the consistency of entrepreneurial behavior is an important criterion for venture capitalists to assess their credibility. In addition, previous scholars have found that the consistency of individual behavior has an impact on the decision-making of venture capitalists. However, the current research has not examined the boundary conditions of impression management and initial trust of venture capitalists. Therefore, this study extends the existing literature on the influence of impression management strategies on initial trust boundaries.The conclusions of this study provide some practical enlightenment for VC-E on how to establish the cooperative relationship of initial trust. Firstly, in the process of venture financing, entrepreneurs must improve the initial trust perception of venture capitalists. Previous studies have shown that the trust of investors can reduce the cost of transactions between the two parties, which is a generalization of fait accomplished. However, the perception of investor trusts is a keen grasp of the external investment environment of entrepreneurship, which is an ex-ante perception. Only by enhancing the initial trust of venture capitalists can we better promote the transactions and cooperation between the two parties. The different entrepreneurial orientation of entrepreneurs can be used as a signal to promote the initial trust of venture capitalists. For this reason, entrepreneurs need to actively shape their own entrepreneurial orientation in the process of starting a business. Entrepreneurs should pay more attention to the continuous changes of the external entrepreneurial environment, have the spirit of risk-taking, dare to innovate, pursue excellence, pay attention to external knowledge learning, strive to improve their business ability, deal with the difficulties in the entrepreneurial process with full entrepreneurial passion, and persevere. Only in this way can he or she describe to venture capitalists that start-ups have better development potential and positive signals of profitability.Next, entrepreneurs should be aware of the difference between the role of impression management strategies in entrepreneurial orientation and initial trust of venture capitalists. In order to reduce the risk investment in trust, venture capitalists always need as much information as possible as decision-making basis when they evaluate the trust of entrepreneurs. In the face of fierce external market competition and high-speed market reaction demand, how to make ideal investment among potential entrepreneurs with low cost and high return needs a high initial trust. Entrepreneurs should be more rational about the driving effect of impression management strategy on the initial trust of venture capitalists. On the one hand, entrepreneurs should actively reveal their own abilities and characteristics; on the other hand, they should also pay attention to the differences in this way of expression. Only reasonable use of impression management strategy can give play to its effectiveness and avoid too low impression management or too high impression management, which causes venture capitalists to question their ability and integrity.Finally, entrepreneurs need to maintain their own behavior consistency in order to reduce the negative impact of perception of hypocrisy. In the initial relationship, there is no empirical knowledge to distinguish the belief of the trusted party from the belief of the environment, and the cognitive consistency is particularly prominent. Faced with the asymmetry of information, when entrepreneurs deliver credible information to venture capitalists through active verbal communication and specific behaviors, they should reduce the uncertainty of this information, maintain the consistency of their own words and actions, and let venture capitalists perceive their sincerity, making them make more benevolent attributions, thereby promoting initial trust. Otherwise, the excessively high perception of hypocrisy will make the effect of the impression management strategy backfire.There are some limitations to this study. First, the research variable data sample is self-reported by venture capitalists. Although there is no serious common method deviation problem, it still exists objectively. In future research, we will consider using questionnaires from both venture capitalists and entrepreneurs for data collection. Moreover, this study analyzes the mediating effect of impression management strategies based only on impression management theory, and subsequent research can adopt other theories to further explore the mechanism. For example, future studies can combine the contextual elements of “guanxi” in China to explore the factors forming trust in entrepreneurs by venture capitalists at different stages and their impact on investment decisions. Finally, the perception of hypocrisy may not be the only boundary condition that affects the relationship between impression management strategies and the initial trust of venture capitalists. Scholars can also discuss the effectiveness of entrepreneurs in adopting acquired impression management strategies or defensive impression management strategies under specific circumstances.Start-ups are at the disadvantage of being “new and weak;” in the early stage of entrepreneurship, the lack of resources restricts their development. How to obtain the support from external resources becomes the main problem for entrepreneurs. In the critical stage of resource acquisition, venture capitalists' initial trust in entrepreneurs plays an important role. High initial trust is conducive to rationally dealing with the emotional relationships about the two parties and to effectively promoting the financing of entrepreneurial projects. The effectiveness of trust has been extensively investigated in entrepreneurship studies. However, compared to the outcomes of trust, it is rare for previous researches to focus on the mechanisms underlying venture capitalists' initial trust in entrepreneurs. Based on signal theory and impression management theory, the study examines the influence mechanism and boundary conditions of different entrepreneurial orientations on the initial trust of venture capitalists.The present study has investigated how different entrepreneurial orientation improves venture capitalists' initial trust through entrepreneurs' impression management strategies. We have found that entrepreneurs' perseverance orientation and passion orientation have an indirect positive effect on the initial trust of venture capitalists through the mediating effect of acquired impression management strategies, while risk-taking, innovation, and proactivity orientation are mediated by defensive impression management strategies. In addition, the perception of hypocrisy not only moderates the relationship between acquired impression management strategies and the initial trust of venture capitalists but also moderates the relationship between defensive impression management strategies and the initial trust of venture capitalists. When the venture capitalist has low perceptions of hypocrisy, the positive effect of acquired and defensive impression management strategies on the initial trust becomes strengthened. We hope this study will enhance our current knowledge on the venture capitalists' initial trust in entrepreneurs and provide some new insights.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.HY, LZ, and YW conceived and supervised the study. HY and LZ wrote the manuscript. HS analyzed the data. YW and SX improved the manuscript. All authors contributed equally to this manuscript and reviewed and approved this manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The growth of abnormal cells in the brain causes human brain tumors. Identifying the type of tumor is crucial for the prognosis and treatment of the patient. Data from cancer microarrays typically include fewer samples with many gene expression levels as features, reflecting the curse of dimensionality and making classifying data from microarrays challenging. In most of the examined studies, cancer classification  accuracy was examined without disclosing biological information related to the classification process. A new approach was proposed to bridge the gap between cancer classification and the interpretation of the biological studies of the genes implicated in cancer. This study aims to develop a new hybrid model for cancer classification (by using feature selection mRMRe as a key step to improve the performance of classification methods and a distributed hyperparameter optimization for gradient boosting ensemble methods). To evaluate the proposed method, NB, RF, and SVM classifiers have been chosen. In terms of the AUC, sensitivity, and specificity, the optimized CatBoost classifier performed better than the optimized XGBoost in cross-validation 5, 6, 8, and 10. With an accuracy of  Brain cancer is the leading cause of death in women under the age of 20 and men under 40 ,2. MoreoMicroarray-based gene expression profiling has proven useful for cancer detection, prognosis, and treatment . In addiCancer microarray data typically contain a small number of samples with many gene expression levels as features, which leads to the curse of dimensionality, making the classification of microarray data a difficult task. The bioinformatics community uses a variety of approaches to classify microarray data using machine learning systems. Most of the examined studies on cancer classification using microarray data sets take cancer classification accuracy into account without disclosing any biological information of the cancer classification process. Few studies have investigated the biological interpretation of microarray data sets in addition to the model classification accuracy. This research aims to bridge the gap between cancer classification and biological interpretation by improving accuracy performance, and the selected significant genes agree with the findings of relevant biomedical studies. This paper proposes a hybrid model based on three different machine learning techniques, including the commonly used ensemble classification methods of gradient boosting , an extrThe experiments show that the proposed model substantially reduces the number of genes required for classification and improves classifier accuracy. Additionally, the proposed hybrid model’s selected genes (features) are biologically interpreted, and the biological interpretation coincides with the findings of relevant biomedical studies. The proposal of a novel ensemble classifier to ensure that the genes selected in our model are biologically interpreted. On top of that, the results are also satisfactory and in line with pertinent biomedical studies. The identification of relevant and non-redundant genes for the biological context by ensemble mRMRs, allowing for enhanced biological interpretations.The analysis of a brain cancer microarray dataset on high-dimensional data using Catboost and XGboost.The optimization of the hyperparameters of the two classifiers using the hyperboot optimizer.The outperformance of Catboost compared to XGboost with regard to the AUC, sensitivity, specificity, and accuracy.The main contributions of this work are:The remainder of the paper is structured as follows: In recent years, multiple pieces of research have used a wide range of machine learning methods for the classification, diagnosis, and treatment of cancer disease. BU-Net was developed by Rehman  and otheBashir et al.  used a fTo overcome the dimensionality problem, Kumar et al.  introduck-nearest neighbor, and decision tree on the diffuse large B cell lymphoma (DLBCL) dataset. Experiments confirmed that the proposed model could successfully compete, with excellent predictions concerning the accuracy, precision, sensitivity, F-measure, and ROC value.Pradana et al.  introducSampathkumar et al.  developeGiven all that has been mentioned so far, all of the algorithms listed above address two major issues: brain cancer classifiers and the curse of dimensionality. However, there is no biological interpretation of the microarray data set discussed in the literature. To the best of our knowledge, this paper is the first paper to provide a consolidated biological interpretation of the results of the proposed work. This section discusses ensemble classification and how to set the hyperparameter values and the minimum redundancy maximum relevance (mRMR) feature selection. The three main components of the proposed method are ensemble classification, hyperparameter optimization, and minimum redundancy maximum relevance (mRMR). First, the ensemble methods use multiple learning algorithms to achieve better predictive performance than if they were used by themselves. Secondly, we have hyperparameter optimization, in which the parameters of the classifier are tuned to find the optimal setting. The third one is minimum redundancy maximum relevance (mRMR), which is a filter-type feature selection method that obtains the best feature set by minimizing the similarities between features and classified variables and by maximizing their correlationsEnsemble learning methods use multiple machine learning algorithms to generate weak predictive results based on the features extracted from various data projections. Following this, the results are fused with various voting mechanisms to achieve better results than any constituent algorithm alone ,33. FiguThe gradient boosting method, which constructs the solution stagewise and solves the overfitting problem by optimizing the loss functions, is one of the most commonly used ensemble classification methods. The main concept of a gradient boosting model is depicted in XGBoost is an efficient gradient-boosted decision tree algorithm . GradienHyperopt is a Python library that implements sequential model-based optimization (SMBO) . HyperopHyperparameter search spaces are typically large multi-dimensional spaces. Hyperopt outperforms grid and random searches, particularly as the search space grows. Within the framework of our proposed model, Hyperopt is used to optimize the settings for the XGBoost and CatBoost hyperparameters. It aims to identify the optimal genes for microarray data analysis and to improve the classification of cancer microarrays.Minimum redundancy maximum relevance (mRMR) is a filter-type feature selection method that obtains the best feature set by maximizing the correlation between the features and the classified variables and by minimizing the correlation between features. The classic function enables the collection of appropriate and non-redundant features with ease . In set Ensemble (mRMR) feature selection implements two ensemble approaches: exhaustive and bootstrap ensemble mRMR. The exhaustive variant of the mRMR heuristic extends it by starting multiple feature selection procedures, with the This section describes the model (as shown in (i)Avoid features in greater numeric ranges dominating those in smaller ranges;Avoid numerical difficulties during calculation;Ensure that each feature is scaled to the range .Preprocessing the dataset (brain cancer microarray). This step is vital to(ii)The data were partitioned into two sets: The training set is used for the training. The testing set is used to test final model 3, initializing CatBoost with specific solution parameters. (iii)CatBoost is used as a feature selector with 8-fold cross-validations . CatBoost calculates the means for each fold.(iv)By setting a threshold, irrelevant features are then removed. Suppose the score of a gene is above the threshold. In that case, the gene will be selected (as seen in (v)The importance value of each gene is registered using a voting process. For example, the gene with index 1 in fold 0 receives an importance value of 1 if the same gene is present in the next fold; then, the gene importance is +1, and so on, for all of the 8-fold cross-validations. After this was applied, voting is conducted 50 genes  Core (TM) i5-7500 CPU with a 32-bit operating system, 4 GB RAM, and the Windows 7 operating system as well as the NumPy, SciPy, Pandas, Keras, and Matplotlib frameworks and Python 2.7 programming language.Molecular profiles from 28 patient samples were analyzed . In addition, an analysis of frozen specimen RNA with oligonucleotide microarrays containing probes for 1070 genes was conducted. Gene expression data are available in the Supplementary Information .k-fold tests were used in the majority of previous experiments. k-fold verification works to find crossed validity by randomly dividing data into k subsets of (approximately) equal size and k-times. As a result, it will run several times, with one subset serving as a test group and the other subset, k-1, serving as a training group  as non-diseased . It is described as AUC shows the area under the receiver operating characteristics (ROC) curve, calculated as Sensitivity, as calculated by This experiment compares optimized (CatBoost and XGBoost) classifiers in the proposed hybrid model to achieve the best hyperparameter of the two classifiers. The Hyperopt optimizer is used. From the data in Number of non-zero genes importance (every fold)..The number of genes selected by embedded SVM (with Redundant), 980 genes.The number of genes selected by embedded SVM (Unique), 671 genes.The final number of genes after we applied voting was 50 genes.In this experiment, CatBoost and optimized CatBoost were compared with the original brain cancer microarray data . Based on the performance metrics in The classic learning algorithms random forest (RF), naive Bayes (NB), and support vector machines (SVM) were used to assess the gene classification accuracy of selected optimal genes by the proposed hybrid model. These learning algorithms were applied to the newly collected dataset, which only included the best genes, and the overall accuracy was calculated. In A subset of genes (features) from the brain cancer data set was biologically interpreted to demonstrate the proposed model’s efficacy in improving critical items such as classification accuracy and for selecting genes with important biological backgrounds. A few classes of important genes derived from microarray technologies were used to diagnose and to provide the prognostic purposes of brain cancer after using the proposed hybrid model’s biological portrait.https://david.ncifcrf.gov/list.jsp (accessed on 18 June 2020) [http://www.geneontology.org/GO.tools.microarray, (accessed on 18 June 2020) are generally considered to be the most inclusive and fastest-growing public repository for grouping functionally related genes. Following that, it can be shown that the proposed approach is the most effective way to pick a large group of genes for brain cancer pathway detection and prognosis.The proposed hybrid model aims to determine crucial gene subsets with the maximum amount of accuracy needed to treat a brain cancer patient. In this segment, the selected group of probe sets could be studied by using the web tool DAVID  ne 2020) ,39. TablIn Brain disorders are becoming a major issue, particularly malignant brain tumors, which significantly impact people’s lives. The brain cancer microarray data have proven to be a complicated classification task due to the small number of samples that have a large number of gene expression levels as features. As part of brain cancer microarray data analysis, the present study proposed an effective and powerful technique for the selection of significant and relevant genes with biomedical relevance. Three distinct techniques were used for classification and prediction . We used the same dataset and three different algorithms to evaluate the performance of the proposed model . The experimental results demonstrate that the proposed hybrid model significantly improves critical items such as classification accuracy and that the selected genes have an important biological background.Furthermore, selecting optimal genes (features) with biological significance can assist biological researchers in brain cancer treatment. The major contributions of this paper are: (a) The application of Catboost and XGboost on high-dimensional microarray data to create a cancer microarray dataset; (b) the use of the hyperboot optimizer to optimize the hyperparameters of the two classifiers, and the outperformance of the Catboost on XGboost in terms of AUC, Sen, Spec, and accuracy; (c) the selection of genes that are non-redundant and relevant to the biological context using ensemble mRMR, which leads to more detailed biological interpretations. Later, the output of the gene subset was combined with the Catboost-selected features. Then, a voting process was applied to obtain unique, informative genes (features) with high relevance and minimum redundancy; (d) the selected genes in our proposed model were biologically interpreted, and the results agree with the findings of relevant biomedical studies. Developing robustness should be a priority for future work.


We investigated the efficacy of monthly alternating injections of aflibercept and bevacizumab (MAAB) for maintenance treatment in patients with neovascular age-related macular degeneration (AMD) who showed improvement with the initial monthly injections but presented with rapid worsening after conversion to bimonthly injections. We included 72 patients with neovascular AMD who showed improvement with loading injections of aflibercept. For maintenance treatment, bevacizumab was administered every alternate month between the bimonthly aflibercept injections in 24 (33.3%) eyes showing worsening (MAAB group). The other eyes were treated with aflibercept (BiA group) bimonthly. Baseline low retinal thickness, thick choroid, and presence of intraretinal fluid were associated with worsening after extending the injection intervals. Visual improvement was lower in the MAAB group than in the BiA group, but the final visual outcomes were comparable. Additional bevacizumab stabilized the early fluctuation of retinal thickness, thus maintaining long-term visual stability without increasing the risk of geographic atrophy or disciform scar until the second year. Previously treated eyes or those with polypoidal choroidal vasculopathy responded less to the initial loading doses and showed worsening under the bimonthly regimen. MAAB was effective in preventing anatomical and functional deterioration when bimonthly aflibercept proved insufficient for the maintenance treatment of neovascular AMD. Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Neovascular AMD is a condition in which abnormal blood vessels grow under the retina and leak fluid. It is an advanced form of AMD where the exudation and scar formation under the chronic inflammation damage the photoreceptor, giving rise to rapid and severe vision loss. . VasculaThis retrospective, consecutive case series was approved by the Institutional Review Board of Asan Medical Center and Yeungnam University Hospital. The study adhered to the tenets of the Declaration of Helsinki. Off-label use of intravitreal bevacizumab was approved by Institutional Review Board of both institutes. Informed consent for each injection was obtained from the subjects.The present study included patients with neovascular AMD presenting between March 2016 and March 2017, at Asan Medical Center and Yeungnam University Medical Center. The study included patients older than 50 years who received three initial loading injections of aflibercept and showed improvement with the initial loading doses, which were part of the maintenance regimen eligible for reimbursement under the Korean National Health Insurance system. Patients with a history of vitrectomy, laser photocoagulation, or photodynamic therapy (PDT), as well as those with other retinal diseases such as angioid streaks, vitelliform macular dystrophy, and retinal vein or artery occlusion were excluded.All patients received three monthly loading doses of aflibercept   injected intravitreally via the pars plana under sterile conditions. After three monthly injections, the patients were divided into two groups according to the change in the retinal fluid status or hemorrhage from month 3 to 4: the bimonthly aflibercept (BiA) group or the monthly alternating injections of aflibercept and bevacizumab   (MAAB) group. If the previous subretinal or intraretinal fluid increased or new fluid or hemorrhage occurred from month 3 to 4, the patients were categorized into the MAAB group, and they were treated with additional bevacizumab injections between the bimonthly aflibercept injections as a maintenance treatment that was part of a fixed regimen. Otherwise, the patients were treated with bimonthly aflibercept injections only (BiA). Follow-up was performed every month in the MAAB group, and every 2 months in the BiA group until 12 months. After 12 months, the treat-and-extend (TAE) aflibercept injection protocol in both groups was adopted according to the recommendations of the Korean National Health Insurance system. If the exudative changes, including the presence of intraretinal and/or subretinal fluid and/or hemorrhage, were absent for more than 2 months, the aflibercept injection interval was extended by 2 weeks to up to 3 months. In the second year of treatment in the MAAB group, additional bevacizumab injections were employed only if the level of retinal fluid or hemorrhage was higher than that at the previous visit as a pro re nata (PRN) regimen at every monthly visit. The treatment protocols are summarized in All patients underwent best-corrected visual acuity (BCVA) measurement with the refraction test throughout the course of treatment. BCVA was converted to the logarithm of the minimum angle of resolution (LogMAR) units. Fluorescein angiography and ICG angiography were performed using a Heidelberg retinal angiography system  to diagnose AMD and determine its subtypes, including typical AMD characterized by the choroidal neovascular membrane, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation. We acquired optical coherence tomography (OCT) images by using the Heidelberg Spectralis OCT system  at every visit.The primary outcome was changes in BCVA in the MAAB and BiA groups during 24 months. The mean changes in central retinal thickness (CRT) from baseline up to 24 months were compared between the two groups. The baseline factors potentially influencing the likelihood of worsening were analyzed after the aflibercept injection interval was increased to 2 months. The secondary outcome was the retinal fluid status during the maintenance period in both the groups. Subgroup analysis in terms of visual and anatomical changes was performed according to the subtypes of neovascular AMD and previous treatment history.t-test or a generalized linear model to determine the relationships between the parameters and outcomes. A p-value < 0.05 was considered statistically significant.All statistical analyses were performed using IBM SPSS Statistics for Windows/Macintosh, Version 24.0 . Categorical variables were presented as numbers and percentages and were analyzed using the chi-square test or Fisher’s exact test. The Wilcoxon signed-rank test was used to compare the mean BCVA or CRT from baseline. Continuous variables, presented as the mean, standard deviation, and range, were analyzed using the two-tailed unpaired Seventy-two eyes of 72 patients with neovascular AMD that showed improvement during the initial aflibercept loading injections were included and followed up for 24 months. Among the 72 eyes, 24 (33.3%) showed worsening of any fluid after increase of the treatment interval to 2 months, and these eyes were categorized into the MAAB group. The remaining 48 eyes (66.7%) were treated with bimonthly aflibercept injections (BiA group). The baseline characteristics of the MAAB and BiA groups are summarized in As the present study enrolled patients who showed improvement with the three loading injections of intravitreal aflibercept, the mean BCVA and CNV size improved in the third month from baseline in both the MAAB and BiA groups, with no significant intergroup differences, as described in p = 0.001, two-tailed unpaired t-test), but no significant difference was observed in BCVA at the follow-up visits between the two groups. When the injection interval was increased to 2 months, visual acuity in the fourth month was worse than that in the third month in both the groups. Although the BiA group showed more improvement in BCVA for 2 years than did the MAAB group (−0.420 vs. −0.075 LogMAR), both the groups maintained visual stability without any fluctuation or deterioration of visual function. Visual outcomes in the first and second year were comparable between the two groups. Even in the second year, when the fixed regimens were changed into the TAE aflibercept and PRN bevacizumab regimens, stable visual acuity was maintained until the second year  and disciform scar  were not different in the MAAB and BiA groups. There was no serious adverse event including endophthalmitis or systemic vascular diseases in both groups.The mean CRT at every follow-up visit decreased from that at baseline and remained stable for 2 years in both the groups . CompareIn the subgroup comparisons, compared to eyes with typical AMD or treatment-naïve eyes, eyes with PCV and previously treated eyes presented with lower response to the three initial loading doses and showed much worsening when the injection interval was increased to 2 months (in the fourth month) in terms of BCVA and CRT . In addip = 0.188, p = 0.001, In the second year, the treatment regimens were changed from the fixed bimonthly protocol to the TAE aflibercept and PRN bevacizumab regimens to reflect real-world treatment circumstances. The present study investigated whether the injection interval could be increased in the MAAB and BiA groups. In the first year, eight aflibercept injections including the loading injections were performed in all patients, and four bevacizumab injections were additionally performed in the MAAB group. In the 2nd year, the number of aflibercept injections was the same in the MAAB and BiA groups (5.3 vs. 5.0, The results of the present study indicate that one-third of the patients with neovascular AMD who responded well to the loading injections of intravitreal aflibercept showed rapid worsening after the extension of the injection interval to 2 months. The findings of the present study are comparable to that of previous studies that reported that 28–31% of eyes showed anatomical worsening after the extension of the treatment interval ,9. The wTo the best of our knowledge, this is the first real world study demonstrating that the MAAB regimen could be effective in preventing anatomical and functional deterioration without increasing the risk of geographic atrophy when bimonthly aflibercept is insufficient for the maintenance treatment. In several countries, aflibercept is not used every month in the poorly responding subgroup under the drug’s governmental guidelines or registration regulations or is not covered by health insurance reimbursements. Our study indicated that the MAAB regimen can stabilize the early fluctuation in retinal thickness. The visual gain achieved during the loading phase was maintained for up to 2 years, even though the fixed regimens were changed into proactive and as-needed regimens in the second year. The as-needed or TAE regimens, rather than continuous monthly or bimonthly injections, tend to be used in daily clinical practice . The secThe underlying mechanism associated with the lower efficacy and shorter durability of 2 months of aflibercept remains unclear. Aflibercept is a soluble decoy receptor with substantially higher affinity than conventional soluble VEGF receptors . AfliberAs aflibercept and bevacizumab differ in their molecular structure and properties, both agents could function complementarily to suppress exudation in neovascular AMD. Multiple reports have demonstrated that patients with bevacizumab tachyphylaxis respond positively to aflibercept . In contNotably, if anatomical worsening occurred in the fourth month, it was not fully restored despite a switch to the monthly alternating injection schedule and was associated with poor visual improvement in the present study. Thus, identifying the risk groups and maintaining the monthly dosing interval are necessary to maintaining the dry macula which leads to long-term visual improvement. The present study demonstrated that low retinal thickness, high choroidal thickness, and the presence of intraretinal fluid at baseline were associated with rapid worsening after the extension of aflibercept injection intervals. In addition, eyes with PCV and previously treated eyes are more resistant to the aflibercept loading regimen and tend to showing worsening when the injection interval is extended. In these cases, we should refrain from extending the aflibercept treatment interval or from adding other treatment agents from the third month.Factors associated with a poor response to or shorter durability of aflibercept in neovascular AMD remain unclear. Higher body mass index and geographic atrophy are considered potential indicators for a poor response to aflibercept . RemnantPCV is considered to respond differently to intravitreal anti-VEGF treatments than does typical AMD ,26. One The present study had several limitations. All patients were Korean. Selection bias can occur in such a retrospectively designed study. Therefore, there was several differences in baseline characteristics between groups. It was not ethically appropriate to divide the worsening group into two independent groups with or without additional bevacizumab. This study lacks the proper control in each group according to the progression in the second year. Moreover, the present study did not control for the types and numbers of anti-VEGF treatments before the eyes were enrolled in the study. As only one treatment regimen was used, the potential value of other regimens, such as those combined with ranibizumab and/or PDT, was not examined. Despite these limitations, the present study included well-designed treatment protocols and extensive follow-up examinations similar to a prospective randomized trial.The present study revealed that, for the first time, the monthly alternating injections of aflibercept and bevacizumab stabilized the early fluctuation of retinal thickness, and thus maintained long-term visual stability in patients with neovascular AMD who presented with rapid worsening after the treatment interval was increased to 2 months. Therefore, under the circumstance that monthly aflibercept is not available, the MAAB regimen could be considered for preventing anatomical and functional deterioration when bimonthly aflibercept injections are not sufficient for the maintenance treatment of neovascular AMD.


Concomitant talocalcaneal coalition (TCC) in idiopathic clubfeet is not well documented in the literature. The purpose of this study was to describe our experience with very early relapsing idiopathic clubfeet associated with TCC. Although cases have been successfully treated with the Ponseti casting method, all recurred within 2 months of removing the final cast. A single-centre cohort of twelve feet in eight patients treated by a single surgeon between 2006 and 2020 was investigated retrospectively. Recurred cavus with variable degrees of equinus was the earliest findings noted. TCC was incidentally detected during the open reduction of the earliest three feet in our series. Afterwards, ultrasonography was advised as a screening tool for detecting an associated anomaly; however, only the use of magnetic resonance imaging (MRI) was 100% accurate in diagnosing concurrent TCC. All coalitions were cartilaginous and the posterior facet was most commonly involved facet. The average age was 18 months for the coalition resection and open reduction of a dislocated talonavicular joint, and the average duration of follow-up was 52 months. None of the patients showed clinical signs of relapse at the latest follow-up. We recommend that an associated TCC should be considered in very early relapsing idiopathic clubfoot cases. Idiopathic clubfoot has been traditionally treated using the Ponseti method of serial manipulation and casting, with initial success rates reported between 85 and 90% . HoweverEarly relapse is usually encountered within the first 2 years of successfully completing the Ponseti treatment ,10,11,12Regarding soft-tissue abnormalities for Ponseti-resistant clubfeet, a recent magnetic resonance imaging (MRI) study showed a wide range of changes, including unique patterns of specific muscle-compartment aplasia/hypoplasia with increased epimysial and intramuscular fat, which were minimally seen in the Ponseti corrected feet . On the Concomitant TCC is not recognized as a possible risk factor for very early relapsing deformity. The purpose of this study was to describe our experience with TCC-associated idiopathic clubfoot and highlight the occurrence of TCC and its prognostic implications. Early diagnosis allowed early definitive treatment in our patients, and we would like to share our results on achieving a plantigrade foot in this study.This study was approved by our hospital’s Institutional Review Board. Electronic medical records and a database containing imaging studies of all patients with congenital clubfoot were examined. From 2001 to 2020, the senior author treated 192 neonates with idiopathic clubfoot using the Ponseti method. Serial manipulation and weekly casting were performed, as described earlier [Eight patients  with twelve idiopathic clubfeet affected by TCC were enrolled in the present study . Left anAfter a radiographic diagnosis of TCC, the patients underwent coalition resection, and adequate soft tissue release to reduce the talonavicular joint and achieve a plantigrade foot. The surgical incisions consisted of two separate medial and posterior zigzag incisions . After aA second medial incision was then made to assess any anterior extent of the coalition. The periosteum with the sheath of the flexor digitorum longus tendon was elevated off the bony prominence and reflected volarly a. After The wound was thoroughly irrigated, and the coalition was cauterised. A fibrin sealant was used as interposition material between the two bony surfaces to prevent any future recurrences of coalition formation e. Any fuAn average of six serial casts were applied, and TA tenotomy was performed in ten feet to correct the primary clubfoot deformity. After removing the final cast, the average relapse time was 7 weeks (range of 3–8 weeks). In all patients, the early presence of cavus with variable degrees of equinus was observed . ForefooIn 2006, the senior author oversaw the first case of early-relapsed idiopathic clubfoot associated with TCC; the patient displayed mild degrees of cavus and equinus within one month of removing the final cast, which was resistant to repeat Ponseti treatment. They subsequently investigated the joints and incidentally found a TCC. A resection of the coalition facilitated the reduction of talonavicular and subtalar joints, and subsequent maintenance of a plantigrade foot was possible. After multiple failed attempts at repeat casting for another two of these patients, the senior surgeon performed a USG to check for the continuity of TA and any anomaly of the hindfoot. However, USG was not diagnostic for an associated abnormality in any of the patients. Therefore, for the following nine feet with similar early recurrence, we performed a non-contrast MRI with minimal sequences to confirm the coalition . We wereThe average age for coalition resection was 18 months . The most commonly involved facet was the posterior facet (4 out of 12 feet), followed by the involvement of both the middle and posterior facets (3 out of 12 feet). The anterior and middle facets were involved in two feet each, and one foot had all three facet joints. The average duration of follow-up was 52 months (range of 6–173 months). At the latest follow-up, none of the patients experienced any clinical findings suggestive of relapse, and all radiographic measurements were within normal range  Table 2.In the first three cases of our cohort, repeat serial manipulation and casting showed only minimal improvement; therefore, the senior surgeon decided to perform a posteromedial release and open reduction of the talonavicular joint. It was during our investigation of the subtalar joints that the coalition was identified and successfully excised. After three such cases, we attempted to establish a protocol to promptly diagnose TCC and allow for the early management of such relapsed clubfeet.The earliest description of idiopathic clubfoot associated with TCC was in isolated case reports ,16 and oWe are unaware of any studies reporting bony risk factors for early relapse after successful treatment with the Ponseti technique. After the senior surgeon experienced three consecutive clubfeet associated with TCC, we used a non-contrast MRI with minimal sequences and found it to be the diagnostic investigation of choice for clubfoot-associated TCC. To allow earlier treatment of relapsed clubfeet, we attempted to develop a protocol to accurately diagnose the underlying pathology. We believe that surgeons can overlook a coalition if they are not aware of this pathology, and increased awareness of this potential anomaly would help achieve early correction of recurred clubfeet that failed to repeat Ponseti treatment.The average number of casting in our series was six, comparable to other reported series of Ponseti-treated idiopathic clubfoot ,23,24. WEquinus deformity has been reported as the most common clinical finding in early relapses within the first 2 years of successfully completing the Ponseti method ,10. HoweAs a routine postoperative assessment of the Ponseti treated foot, the senior surgeon began to use USG to examine the continuity of the TA since 2006 . Given tEarly treatment with a TCC resection and reduction of the dislocated joint has been successful for all our patients. Even after the child began walking, there were no clinical signs of relapse, and the radiographic measurements of anteroposterior and lateral talocalcaneal angles were within normal limits at the latest follow-up. However, our observations have limitations related to the small number of patients, limited follow-up, and inability to predict the long-term results of this study. Furthermore, we suspect that each facet of the subtalar joint in these patients may not become normal even after coalition resection, and the potentially malformed joint orientation may cause another deformity as the child grows.We recommend that surgeons maintain a high degree of suspicion for the talocalcaneal coalition in cases of very early relapsing idiopathic clubfoot with cavus and variable degrees of equinus, as this pathology may be more common than previously documented. MRI is the gold standard investigation and should be performed for definitive diagnosis even in the absence of abnormal findings with ultrasonography.