The purpose of radiation therapy (RT) is to cover tumor tissue homogeneously with a planned dose while minimizing the dose to the surrounding healthy tissue . At pres2+) in ferrous sulphate solutions are dispersed throughout the gel matrix, while in the second one, monomers (such as acrylamide), are dispersed in the matrix. The radio-inducted variations can be read out by magnetic resonance imaging (MRI), x-ray computed tomography (CT), optical scanning, and ultrasonography. Despite extensive research in recent decades, gel dosimeters have yet to achieve widespread clinical acceptance, mainly because of three major practical concerns: the toxicity of active materials, oxygen sensitivity of the dose response, and the spatial instability of dose information.In this scenario, “Gel dosimetry” is the most promising tools for the evaluation of 3D high-spatial-resolution dose distributions, and the studies regarding these materials represent the starting point for developing performance and innovative systems . “Gel doA number of gel dosimetry systems have been developed over the years with differing mechanisms of operation and varying degrees of success in alleviating the practical issues, inhibiting a clinical application.This current Special Issue is a thorough collection of articles dealing with the synthesis and characterization of hydrogels, of which the authors show the mechanisms of action and prospective applications for 3D dosimetry. The overview presented in this Special Issue would not be complete without mentioning novel approaches for the characterization and modeling of hydrogels for medical applications.Gels, belonging to the “Gel Analysis and Characterization” Section and titled “Gel Dosimetry”, was to collect original research manuscripts that describe cutting-edge developments in hydrogel-based materials for dosimetry and their translational applications, as well as reviews providing updates on the latest advancements in this field.With this in mind, the goal of this Special Issue of A series of manuscripts have been submitted to the Special Issue, and 11 of them have been accepted for publication. The final collection includes eight original research manuscripts and three reviews by authors from ten different countries. The contents of the published manuscripts are briefly summarized below.Zirone et al. [In the article of e et al. , entitleMerkis et al. [In the article of s et al. , a uniqude Silveira et al. [The manuscript entitled “Three-Dimensional Dosimetry by Optical-CT and Radiochromic Gel Dosimeter of a Multiple Isocenter Craniospinal Radiation Therapy Procedure” by a et al.  proposedSoliman et al. [n et al. , using UScotti et al. [The manuscript of i et al.  aims to i et al.  and gluti et al.  dosimeteToyohara et al. [In the manuscript of a et al. , radioacRabaeh et al. [2) on the performance of N-(hydroxymethyl)acrylamide (NHMA) polymer gel dosimeter. The dosimeter was exposed to doses of up to 10 Gy with a radiation beam-energy of 10 MV, and the relaxation rate (R2) parameter was utilized to explore the performance of irradiated gels.The manuscript of h et al. , entitleMizukami et al. [1 relaxation time also remains an important goal in clinical examinations. Low-noise, high-resolution 3D mapping of T1 relaxation times could not be achieved in a clinically acceptable time frame (<30 min). The authors also demonstrated that the whole three-dimensional dose distribution could be roughly evaluated within the conventional imaging time (20 min) and the quality of one cross-section.In the study of i et al. , the autOur Special Issue also covers some high-quality review articles that complement the recent literature regarding 3D gel dosimetry ,18,19.In the review article entitled “Recent Advances in Hydrogel-Based Sensors Responding to Ionizing Radiation” , the autThe review article entitled “Radiation Dosimetry by Use of Radiosensitive Hydrogels and Polymers: Mechanisms, State-of-the-Art and Perspective from 3D to 4D” by De Deene  providesMacchione et al. [The review article entitled “Chemical Overview of Gel Dosimetry Systems: A Comprehensive Review” by e et al.  aims to In conclusion, we were very pleased to guest edit this Special Issue, as it collects relevant contributions that reflect the increasingly widespread interest in hydrogels and related applications in the field of “3D Dosimetry” and “Radiation Therapy”. We hope that this Special Issue can reach the widest possible audience in the scientific community and contribute to further boosting scientific and technological advances in the intriguing world of hydrogels as well as their multidisciplinary applications. Finally, we wish for this Special Issue to help its readers to conceive both new and improved ideas about “Gel Dosimetry” in their respective fields.


The coronavirus disease (COVID-19) pandemic has highlighted the close relationship between infection and kidney injury. Infections induce kidney parenchymal injury directly or indirectly through the various mechanisms of several renal diseases. This Special Issue, entitled “Infection and the Kidney,” focuses on this important and expanding topic of research, providing research and updated reviews on kidney injury observed in association with ongoing or past infection.Masset et al.  describePorphyromonas gingivalis, in IgAN by showing a higher presence of these bacteria within the tonsils of patients with IgAN than in those of patients with simple tonsillitis, together with experimental data from a mouse model. Nagasawa et al. [IgA nephropathy (IgAN) is a rare disease for which a link between focal infection and kidney inflammation has been demonstrated in humans, as evidenced by the widespread use and efficacy of tonsillectomy in Japan. Its efficacy has been so great that most centers in Japan have begun using tonsillectomy plus steroid pulse therapy as the standard treatment for IgAN. The developers of this treatment, Hotta et al. , contriba et al.  also conStaphylococcus aureus (MRSA)-infection-associated glomerulonephritis. Yoshizawa et al. [Streptococcus. Therefore, NAPlr could be used as a general biomarker of bacterial IRGN (Regarding infection-related glomerulonephritis (IRGN), two elegant reviews were included: one written by Yoshizawa et al. , the disa et al.  describeial IRGN . FurtherFinally, Uchida et al.  summarizA detailed understanding of the mechanisms underlying the relationship between infection and the kidneys is important because it may also lead to the elucidation of the pathogenic mechanism of idiopathic renal diseases. This is an area where knowledge is expanding, and further development is expected. Therefore, a second edition of the Special Issue, “Infection and the Kidney 2.0,” is currently being compiled .


RVF poset al.  showed tet al. .Regardless of the timing of t-RVAD placement, there is undeniably an especially challenging subset of patients in whom wean from t-RVAD support is not tolerated and will require ongoing, durable right ventricular support. The total artificial heart (TAH) option has many limitations based on its large size, large pneumatic drive system limiting mobility, and geographic availability . An alteet al. [et al. [et al. [Milano et al.  reportedet al. . Urganci [et al.  have sha [et al.  describein situ t-RVAD graft. In addition, the team eloquently show a technique of ring augmentation to make up the discrepancy between inflow cannula length and right atrial size.Herein, the Berlin group describes a patient who presents with biventricular failure due to ischaemic cardiomyopathy and ultimately is taken for HM3 LVAD implantation . The decAuthors make use of excellent visuals to contextualize the intraoperative challenges in this complex clinical scenario and provide simple techniques used to mitigate them. Clearly not for the ‘faint-hearted’, this approach is becoming an important addition to the armamentarium of every practicing mechanical circulatory support surgeon.


Careful observation of the QT interval is important to monitor patients with long QT syndrome and during treatment with potentially QT-prolonging medication. It is also crucial in the development of novel drugs, in particular in case of a potential side effect of QT prolongation and in patients with increased risk of QT prolongation. The 12-lead electrocardiogram (ECG) is the gold standard to evaluate cardiac conduction and repolarization times. Smartwatches and smart devices offer possibilities for ambulatory ECG recording and therefore measuring and monitoring the QT interval. We performed a systematic review of studies on smartwatches and smart devices for QTc analysis. We reviewed PubMed for smartwatches and smart devices that can measure and monitor the QT interval. A total of 31 studies were included. The most frequent devices were (1) KardiaMobile 6L, a Food and Drug Administration-approved device for QTc analyses that provides a 6-lead ECG, (2) an Apple Watch, a smartwatch with an integrated ECG tool that allows recording of a single-lead ECG, and (3) the Withings Move ECG ScanWatch, an analog watch with a built-in single-lead ECG. The KardiaMobile 6L device and the Apple Watch provide accurate measurements of the QT interval, although the Apple Watch is studied in standard and non-standard positions, and the accuracy of QT measurements increased when the smartwatch was moved to alternative positions. Most studies were performed on patients, and limited results were available from healthy volunteers. In 1957, Jervell and Lange-Nielsen described a case of a family in which QT prolongation was found in multiple children and who subsequently died in infancy without any evidence of cardiac pathology at autopsy , 3. As ahttps://pubmed.ncbi.nlm.nih.gov) for studies published on the use of smart devices for QTc analysis until September 30, 2022. For reporting and methodology, the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used (We reviewed PubMed (ere used . Terms “N = 16). Five studies examined the Apple Watch. Another smart watch (SW), the Withings Move ECG ScanWatch, was examined in three studies. A graphic representation of the three most studied devices is shown in The initial search identified 1,071 studies. After screening titles, 43 articles were considered for further review. After reviewing the 43 articles, 12 articles were further excluded. The search strategy is shown in r = 0.856; p < 0.001) in lead II. The absolute difference between QTc values was <10 ms in 55% of the subjects. A mean QTc ≥480 ms in lead II on the 12-lead ECG was found in six subjects. The sensitivity and speciﬁcity for mECG QTc prolongation in lead II were 80% and 99%, respectively (n = 203). The authors concluded that using a 6-lead mECG enables measuring the QT interval with good accuracy compared with the standard 12-lead ECG. Frisch et al. (p = 0.15). An excellent agreement and no statistically signiﬁcant differences in the QTc interval measurement was found in this study. It was demonstrated that the KM-1l device has adequate precision and agreement compared to the standard 12-lead ECG. Minquito-Carazo et al. (p < 0.001) shorter in the KardiaMobile 6-lead ECG than in the 12-lead ECG. Beers et al.  is a wireless mobile ECG (mECG) device that can directly record a 6-lead ECG, which consists of leads I, II, and III and also augmented Vector Left (aVL), augmented Vector Foot (aVF), and augmented unipolar right arm lead (aVR). It is a small (9.0 cm × 3.0 cm × 0.72 cm) device that consists of three electrodes each on both the top surface and the bottom surface. Electrodes on the top surface make contact with both thumbs, and electrodes on the bottom surface make contact with either the left knee or the left ankle. KardiaMobile 6L can subsequently be connected to the corresponding application through Bluetooth on mobile devices such as tablets and smartphones to record a 30-s 6-lead mECG. It then provides an automated assessment of heart rate and heart rhythm . The FDAh et al.  publisheh et al.  publisheh et al.  investigh et al.  evaluateo et al.  evaluateo et al.  assessedo et al.  comparedo et al.  comparedo et al.  present s et al.  determins et al.  validates et al.  trained s et al.  describeN = 100). Apple Watch lead I was obtained with the watch on the left wrist, and lead II was obtained with the watch on the left ankle. Furthermore, the simulated lead V6 was recorded with the watch on the left lateral chest. Adequate QT measurements were observed in 85% of the patients when the SW was worn on the left wrist. This number of adequate measurements increased to 94% when the SW was moved to alternative positions. Chinitz et al.  is an analog watch with an in-built single-lead ECG. It offers, without manual measurement of the SW-ECG or the need for any other software, an automated analysis of the corrected QT interval . An artiR2 = 0.89). Carter et al.  with possibilities for ECG and QTc measurements. When an SW is worn on the wrist, which is common practice, the device can only provide lead I recording, which has significant limitations. Historically, measurement of conduction intervals is preferably performed in lead II , which i testing . MeasureSmartwatches and smart devices offer possibilities for monitoring the QT interval and could be of great additional value. Compared to a 12-channel ECG, patients can record an ECG themselves, which is also possible at home. Results differ from device to device, but some devices can provide comparable results with the gold standard 12-lead ECG and allow adequate QT measurements. Given that smartwatches are already owned by many people and offer additional functionalities, these are promising devices. However, it is recommended to not only measure the QT interval from standard lead I but also at least from lead II and preferably one of the precordial leads. Further studies are needed to evaluate and validate QTc monitoring in healthy subjects and patients. While much research has been done into detecting atrial fibrillation with an SW, this review proves that reliable measurement of the QT interval is also possible. This can have an important impact on drug safety monitoring and monitoring of patients at risk for QT prolongation and offers opportunities in drug research. These devices have the potential to lead to future clinical applications in the evaluation of any drug-induced arrhythmogenicity related to prolongation of the QT interval, needing close monitoring of QT intervals. Before they can be used in daily clinical practice for antiarrhythmic drug initiation, alerts for QT prolongation or arrhythmic events need to be prospectively studied.


Inflammation and hypertrophy of the ankle joint's synovial lining can occur due to various causes. Chronic pain and degenerative changes may be due to synovitis causing clinical manifestations through traction on the joint capsule. The failure of conservative treatment for at least six months indicates arthroscopic debridement, which can provide significant pain relief without the morbidity of extensive surgical exposures. This study was therefore conducted to establish the functional results of arthroscopic debridement of the ankle joint in synovitis. Fifteen patients with chronic ankle pain who had not responded to conservative treatment for approximately six months were included in the study. Arthroscopic debridement was performed using a shaver blade, followed by a postoperative ankle physiotherapy regimen. Patients were assessed preoperatively and postoperatively using the AOFAS, FADI, and VAS scores, with a mean follow-up period of 26 months. There was a significant improvement in the final clinical outcomes of the patients. The post-operative VAS score improved to 2.20±0.56 (2-4) , the AOFAS score was 86±8.25 (65-98) , and the FADI Score was 86.93±7.35(70-96) . Thirteen patients (86.67%) achieved outstanding or good results, while two had fair results, according to Meislin's criterion. One patient reported a superficial wound infection, which subsided with antibiotic therapy. The study findings indicate that arthroscopic ankle debridement is an efficient method to treat persistent ankle discomfort induced by synovitis, and it has a low postsurgical complications rate, quicker recovery, and less joint stiffness. Inflammation and hypertrophy of the ankle joint's synovial lining can occur as a consequence of inflammatory arthritis, infection, and degenerative or neuropathic diseases. When chronic pain and degenerative changes are evident, it is important to keep in mind that synovitis may be present, which can cause clinical manifestations either directly or indirectly through traction on the capsule. Trauma and joint overuse can cause pain and swelling due to generalized inflammation of the joint synovium . In mostSome patients experience continuous ankle discomfort and swelling without evidence of ankle instability. An arthroscopic examination occasionally reveals localized synovitis . A cliniThere is controversy regarding how to treat a patient who sustains an ankle injury and experiences prolonged symptoms despite a stable ankle joint. In recent years, due to advancements in small joint arthroscopy and the introduction of suitable instruments and scopes for smaller and tighter joints, arthroscopic debridement has gained popularity due to its minimally invasive nature, low morbidity, less joint stiffness, and faster recovery. Currently, ankle arthroscopy has been successfully used to treat various disorders, such as loose bodies, talar dome defects, degenerative disorders, and posttraumatic conditions -8. HowevThis prospective study was conducted at the Department of Orthopedic Surgery from November 2019 to December 2022. It involved fifteen patients, including 10 males and 5 females, with a mean age of 38.80±15.68 years (ranging from 20 to 65 years). These patients experienced chronic ankle pain that did not respond to conservative treatments such as Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and repeated courses of physiotherapy for approximately 6 months. The exclusion criteria comprised patients with localized soft-tissue infection, tenuous vascular status, and ankle instability.A comprehensive personal and clinical history was obtained from each patient, followed by a thorough examination that included the Ankle Anterior Drawer test and Talar tilt test to assess ankle instability. To evaluate foot disability, we calculated the American Orthopaedic Foot and Ankle Society (AOFAS) Score and the Foot and Ankle Disability Index (FADI) score. In addition, the Visual Analogue Scale (VAS) score was calculated to document the severity of pain. All patients had persistent ankle pain with intermittent localized swelling. All ankles were stable on stability tests. An X-ray examination was done to assess the patient preoperatively. A senior surgeon performed all the operations, using a tourniquet in each case. The joint surfaces were carefully examined  A-B. Theet al. [The study of Duan et al.  was usedThe average age of the patients was 38.80±15.68, ranging from 20 to 65 years. 10 male and 5 female patients were included in our study . These iMeislin’s criteria and the AOFAS, FADI, and VAS scores were calculated for each patient preoperatively. In the pre-operative group, 6 patients (40%) were in the “Fair” category and 9(60 %) were in the “Poor” category of AOFAS grading . Eight pPostoperatively, we did a final evaluation of the patients. There has been significant improvement in scoring and pain assessment. Six (40%) patients were in the “Excellent” category, 7(46.67%) patients were in the “Good” category, 1(6.67%) patient was in the “Fair” category, and 1(6.67 %) was in the “Poor” category of AOFAS grading . FourteeAnkle arthroscopy has gained popularity as a diagnostic and therapeutic procedure during the last decade. Compared to other major joints like the knee and shoulder, ankle arthroscopy is still in its early stages. All intra-articular structures of the ankle can be directly seen with ankle arthroscopy without requiring an arthrotomy or malleolar osteotomy. The capacity to perform ankle diagnostic and surgical arthroscopy has improved due to technological advancements and a complete understanding of anatomy. It is a more desirable procedure than open arthrotomy due to the lower morbidity and quicker recovery time. The ankle joint of the patients we evaluated showed superfluous and often inflamed synovial tissue. The cause of synovitis in these patients was unknown and might be multifactorial. Most of them previously suffered an ankle sprain. It may have arisen as a result of an acute event or repeated ankle sprains irritating the joint. Hemarthrosis resulting in an acute inflammatory response could proceed to chronic synovitis with repeated joint irritation if previous injuries were present. They did not show any signs of ligamentous instability. In 86.67% of our patients, arthroscopic debridement resulted in symptom alleviation.et al. [et al. [et al. [et al. [Ankle arthroscopy was suggested by Ogilvie-Harris, Gilbart, and Chorney  for patiet al.  found th [et al.  reported [et al.  suggeste [et al.  discoveret al. [et al. [Ahn et al.  performe [et al.  did an aet al. [et al. [et al. [In their study, Woo Jin Choi et al.  conducteet al. . They ob [et al.  conducte [et al. , 15 patiIn our study, the mean pre-operative FADI score was 48.53±18.82 (13-65), and the mean post-operative score was 86.93±7.35 (70-96).et al. [et al. [In a study by Woo Jin Choi et al. , where a [et al.  investiget al. [et al. [et al. [et al. [et al. [In a study conducted by Hassan et al.  involvin [et al.  found 90 [et al.  reported [et al.  reported [et al.  also rep [et al.  and comp [et al. . Fair reCommon complications reported during ankle arthroscopy in other studies are superficial peroneal nerve injury during anterolateral portal placement  and suraFinally, we believe that arthroscopic ankle debridement can successfully treat persistent ankle discomfort induced by synovitis, and it has a low postsurgical complications rate, quicker recovery, and less joint stiffness.


Machine Learning and AI for Sensors”  Issue of the Sensors journal. The primary aim of this Special Issue is to demonstrate the recent advances related to machine learning and AI methods on sensors as well as investigate the impact of their application in a variety of hard real-world problems. In total, twelve (12) research manuscripts were accepted for publication after going through a careful peer-review process based on contribution and quality criteria. All accepted manuscripts possess significant elements of novelty and enclose several application domains, which provide the readers with a glimpse of the state-of-the-art research in the machine learning area.This article summarizes the works published under the “In recent decades, new advances in machine learning (ML) and artificial intelligence (AI) have covered areas from zero- and single-shot algorithms ,2,3 to dHowever, the increasing challenging necessities of the industrial sector as well as considerable needs of this data-driven era led to the development of new, efficient and robust methodologies and approaches. Along this line, novel AI and ML algorithms are needed, such us new data quality techniques, new clustering, classification and reinforcement learning methods; in addition, distributed AI algorithms are required and different strategies are needed to embed these algorithms in sensors.A novel approach to image recoloring for color vision deficiency” and it is authored by Tsekouras et al. [The first paper is entitled “s et al. . In thisXcycles backprojection acoustic super-resolution” and it is authored by Almasri et al. [The second paper is entitled “i et al. . The autDecision confidence assessment in multi-class classification” and it is authored by Bukowski et al. [The third paper is entitled “i et al. . In thisBoosting intelligent data analysis in smart sensors by integrating knowledge and machine learning” and it is authored by Łuczak et al. [L-neurons, while the latter is a fully-connected three-layer feedforward neural network. The authors provided a comprehensive experimental analysis, which showed that the proposed hybrid structure successfully combines learning and knowledge and provides high recognition performance even for a small number of training instances. Finally, the authors stated that since the proposed L-neurons are able to learn through classical backpropagation processes, the proposed architecture is capable of updating and repairing its knowledge.The fourth paper is entitled “k et al. . In thisHyperspectral image classification using deep genome graph-based approach” and is authored by Tinega et al. [The fifth paper is entitled “a et al. . The autA heterogeneous RISC-V processor for efficient DNN application in smart sensing system” and is authored by Zhang et al. [The sixth paper is entitled “g et al. . In thisA convolutional autoencoder topology for classification in high-dimensional noisy image datasets” and is authored by Pintelas et al. [The seventh paper is entitled “s et al. . In thisMulticlass image classification using gans and cnn based on holes drilled in laminated chipboard” and it is authored by Wieczorek et al. [The eighth paper is entitled “k et al. . The autA comprehensive survey on nanophotonic neural networks: architectures, training methods, optimization and activations Functions” and it is authored by Demertzis et al. [The ninth paper is entitled “s et al. . In thiss et al.  for everMulti-agent reinforcement learning via adaptive Kalman temporal difference and successor representation” and is authored by Salimibeni et al. [The tenth paper is entitled “i et al. . The autAn IoT-enabled platform for the assessment of physical and mental activities utilizing augmented reality exergaming” and it is authored by Koulouris et al. [The eleventh paper is entitled “s et al. . In thisA robust artificial intelligence approach with explainability for measurement and verification of energy efficient infrastructure for net zero carbon emissions” and is authored by Moraliyage et al. [The twelfth paper is entitled “e et al. . In thise et al. . The proConclusively, we point out that the rationale and motivation behind this Special Issue was to provide a minor contribution to the existing literature about machine learning and AI methods for sensors. The examination of a variety of interesting proposed methodologies led to the presentation of a diverse range of novel strategies. Our great expectation is that the presented techniques and approaches, which were demonstrated in this Special Issue, will be found to be constructive and deeply appreciated by the scientific and industrial communities. Finally, the guest editors express their sincere gratitude to all authors for their high-quality contributions as well as the publisher and members of staff for their invaluable advice and support, which contributed in a decisive manner to enriching the quality of this editorial paper.


Social cognition and mental health among children and youth” aims to provide a forum to improve research in this field and its contribution to health psychology, the understanding of risk and protective factors, and the exploration of innovative psychosocial interventions to benefit children and youth's health and wellbeing. People's feelings and social experiences are very influenced by their social, cultural, educational and autobiographical contexts.This editorial comment on “Long-term effects of stress, such as COVID-19, have the potential to seriously endanger developing children's and youth's social cognition and mental health , the 18 articles on this Research Topic highlight the individual and contextual factors that can affect the mental health and psychological wellbeing of these age-groups. In this section, we refer briefly to the themes and novel contributions of these 18 articles.Zeng et al. characterized post-traumatic growth and academic burnout and “the moderating role of core belief challenge among adolescents in an ethnic minority area in China during the COVID-19 pandemic” (p. 1). Fang et al. explored an audience's emotional experience and sharing of audio-visual artistic works during the COVID-19 pandemic. In a sample of college students, Chen S. et al. “explored the mediation and moderation effects on the relationship between different social media usage patterns, emotional responses, and consumer impulse buying during the COVID-19 pandemic” (p. 1). Lin et al. surveyed a large sample of Chinese adolescents and, based on health-related correlates, revealed the important role of negative problem orientation. Feng and Zhang explored “the effect of perceived teacher support and peer relationships on the mental health of Chinese university students, examining the mediating effects of reality and Internet altruistic behaviors on these relationships” (p. 1). Yue et al. explored the influence of peer actual appraisals on moral self-representations through peers' reflected appraisals among Chinese adolescents aged 12–14. Li M. et al. examined the relationship between empathy and altruistic behavior and their underlying mechanisms in Chinese undergraduate and graduate students. Yan et al. offered a theoretical model of how perceived control and sense of power affect adolescents' acceptance intention of intelligent online services through their perceived usefulness. Zhu et al. conducted behavioral and event-related potential experiments in China to illustrate “how young females with facial dissatisfaction process different levels of facial attractiveness” (p. 1). Chen X. et al. “revealed the effect of family cohesion on adolescents' engagement in school bullying and its mechanism of action, providing a theoretical basis for preventing and reducing the occurrence of school bullying incidents” (p. 1). Li A. et al. examined how a father's presence affects an adolescent's social responsibility, and their quality of interpersonal relationships. Li T. et al. “constructed a moderated chain mediation model to investigate the influence of childhood psychological abuse on relational aggression among Chinese adolescents” (p. 1). Zhang et al. demonstrated that photographic intervention could effectively improve positive affect and mitigate negative affect of college students during the COVID-19 pandemic. Wang et al. “showed that subjective wellbeing was positively correlated with social trust, trust in people, self-compassion, and social empathy” (p. 1), in a sample of first-generation Chinese college students. Hua and Zhou examined the relationship between personality assessment and mental health, via sequential mediation path involving the Barnum effect and ego identity. Liu et al. used a multi-methods approach “to analyze the mediating effects of social comparison and body image on social media selfie behavior and social anxiety in Chinese youth group” (p. 1). Fan et al. explored how relationship-maintenance strategies affect burnout in adolescent athletes, “including the potential mediating effects of the coach–athlete relationship and basic psychological needs satisfaction” (p. 1). Lastly, van Grieken et al. evaluated the longitudinal association between life events occurring before the second year and the risk of psychosocial problems at 3 years of age in Netherlands.The papers on this Research Topic show how understanding the fundamental cognitive/social processes and the applied/clinical situations may help unify and expand our knowledge of Social Cognition and Mental Health throughout childhood and adolescence. However, the research herein is not exhaustive, and results must be weighed against the many conceptual and methodological constraints indicated in the publications. There are also geographic and cultural limits since most of the investigations were done in China. However, we believe that by offering an overview of the topic and emphasizing the most recent achievements, this Research Topic/eBook will be useful to both beginners and specialists toward improving the mental health of disadvantaged children and youth around the globe.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that affects a patient for their entire life. Effective treatments for IBS are scarce, leading to an increased interest in alternative treatments such as osteopathic manipulative treatment (OMT). OMT uses hands-on treatment to reduce pain through various methods. By focusing on visceral techniques, OMT can restore autonomic homeostasis and increase lymphatic flow. This literature review aims to investigate the efficacy of visceral OMT in reducing the severity of IBS symptoms. Five primary research studies were evaluated in this analysis. The concluding results show that visceral OMT effectively reduces the symptoms of IBS and improves patients' quality of life. Therefore, OMT should be considered an alternative therapy for treating IBS. Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) condition that affects approximately 5-20% of the population and has an annual incidence of 196-260 per 100,000 [IBS can be classified as a “gut-brain axis” disorder because the processing of visceral stimuli is altered and sub-optimal in function, leading to the majority of symptoms patients experience . TherefoThis review aims to answer the effectiveness and safety of the use of osteopathic treatment in reducing the severity and symptoms of IBS in patients.This article was previously presented as a poster at the 2023 Florida Osteopathic Medical Association Research Poster Competition on February 3rd, 2023, the LECOM Bradenton Interprofessional Research Day on April 27, 2023, and at the 2023 FMA Poster Symposium on July 29, 2023 (Appendices).MethodsPrimary research studies and meta-analyses examining the effect of OMT on the symptom severity of IBS were identified using academic search engines, including Google Scholar and Osteopathic Research Web by E.G. in August 2022. Keywords “osteopathic visceral techniques” and “Irritable Bowel Syndrome” were utilized in each search engine. Nine primary research studies and one meta-analysis were found using Google Scholar, and three primary research studies were found using the Osteopathic Research Web. These were all reviewed by C.L., J.B., A.J., M.G., E.G., and J.T. The articles most relevant to the research question were determined based on described inclusion and exclusion criteria. Our study included only those research papers that met two criteria: First, they utilized the Rome III Criteria, and second, they had a minimum of five participants. Case studies and articles published in languages other than English were excluded from our study. IBS studies that did not relate to OMT were also excluded from our study. Overall, two primary research studies and one meta-analysis were included from Google Scholar, and one primary research study was included from the Osteopathic Research Web. We came across a fifth study, Hundscheid et al., which was referenced in the research study by Attali et al. Based on the inclusion and exclusion criteria discussed, we included Hundscheid et al. in our analysis. Results were analyzed by comparing the statistical significance of improvement in IBS symptoms following OMT. A flow diagram of included studies is detailed in Figure ResultsFour out of the five studies were randomized controlled studies, and the fifth study was an intervention study. Each study used different methods to analyze outcomes. Attali et al. and Florance et al. analyzed IBS symptom severity, Steiner used the Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) and IBS symptom severity (IBS-SS) questionnaires, and Hundscheid et al. and Stiedl et al. used score sheets such as the Likert/visual analog (VAS) scale -7. AdditAttali et al., Florance et al., Hundscheid et al., and Stiedl et al. demonstrated statistical significance with P values less than 0.01, as seen in Table DiscussionA combined analysis of all research studies indicates that OMT has the ability to ease IBS symptoms. Attali et al. discovered that visceral OMT alleviated constipation, diarrhea, abdominal distension, rectal hypersensitivity, and abdominal pain . SteinerThere are several theories on how visceral manipulation can improve the symptoms of those with IBS. After somatic manipulation treatment, some physiologic properties improve. These include increased fluid dynamics and nutrition to supply tissue, relaxing smooth muscle in fascia and ligaments, increased blood flow, and improved lymphatic drainage . AdditioAttali et. al, Florance et al., and Hundscheid et al. reported no adverse side effects for groups treated with OMT -6. SteinLimitationsOverall, osteopathic treatment use for IBS symptoms has shown a great response, with no known adverse effects. Even so, there are some limitations in this review on osteopathy for the treatment of IBS. The studies reviewed used different visceral and soft tissue techniques as opposed to standardizing a single technique. The techniques that were conducted varied in length of time and frequency, which may have contributed to the greater degree of symptom resolution in some sample groups. Researchers utilized varying numbers of osteopathic physicians for treatment. The studies employed various severity scores and did not compare different types of severity scores in the treatment of IBS. Lastly, our sample size was small. A larger sample size would have increased the power of this study and decreased the margin of error.This review demonstrates a correlation between the benefits of visceral osteopathy and a reduction in the severity of IBS symptoms. The OMT performed did not appear to cause any side effects. Therefore, OMT may be considered a safe alternative or adjunct in the treatment of patients with IBS. However, more research is needed due to a limited number of randomized controlled studies relating to the effectiveness of OMT in alleviating IBS symptoms. Future studies will help demonstrate a stronger causal positive relationship between the benefits of visceral OMT and the reduction of IBS symptoms.


This Special Issue, focused on a collection of papers on “attacking cancer progression and metastasis”, is devoted to communicating current knowledge about the cellular and molecular mechanisms involved in cancer progression and metastasis, as well as suggesting new targets for possible future therapeutic interventions. It aims to provide ample scope for new ideas on how to block or weaken processes of cancer progression to its final stage. Nine interesting scientific papers from basic research covering a broad spectrum of cancer types  and seven reviews offer an extensive view on various aspects of possible targetable mechanisms leading to possible future interventions.In the research article “Anti-Stem Cell Property of Pterostilbene in Gastrointestinal Cancer Cells”, Shiori Mori et al.  showed tMonika Barathova et al.  describeAmy Scholze et al.  proved tThe up-regulation of the receptor for advanced glycation end products (RAGE), in the absence of stimulation by external ligands, has been shown by Priyanka Swami et al.  to modulMargarite Knyazeva et al.  used couTargeting collagen prolyl 4-hydroxylase 1 (C-P4H1) is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. Shike Wang et al.  developeThe role of methionine aminopeptidase 2 (MetAp2), an intracellular enzyme known to modulate angiogenesis, in lymphangiogenesis has been described by Rawnaque Esa et al. . The genAmong the reviews published in this Special Issue, Olamide T. Olaoba et al.  offered Eleonora A. Braga et al.  analyzedSylwia Tabor et al.  discusseBoris Mravec et al.  providedThe review “New Insights into Therapy-Induced Progression of Cancer” written by Polina V. Shnaider et al.  summarizMarisol Miranda-Galvis and Yong Teng  aimed toFinally, Sona Ciernikova et al.  summariz


Collectively, urological malignancies account for a considerable proportion of cancer cases worldwide. Among them, prostate cancer (PCA) is the most frequently diagnosed cancer in men, while bladder cancer (BCA) and renal cancer (RCC) rank among the top 10 most prevalent cancers globally. The high incidence rates pose a significant public health problem. The treatment of urological malignancies often involves complex approaches such as surgery, radiation therapy, chemotherapy, and targeted therapies. However, a better understanding is needed to further enhance the therapeutic management and to improve outcomes for patients. In this editorial, we examine and analyze the key findings from the original articles published in the Special Issue “Insights into Urologic Cancer”. These studies contribute to advancing our understanding of urological malignancies and hold significant implications for patient care and outcomes.Jirásko et al.  exploredHistopathological discrimination of chromophobe RCC and oncocytoma may be challenging due to a similar appearance. Bin Satter et al.  developeMetastasis is a major challenge in RCC, often associated with poorer outcomes. Sanders et al.  investigTyrosine kinase inhibitors have revolutionized RCC treatment, but resistance remains a challenge. Ding et al.  highlighDJ-1 is involved in various cellular processes and has been implicated in cancer development and progression. Hirano et al.  studied The study by Gutierrez et al.  sheds liThe introduction of the antibody–drug conjugates enfortumab vedotin targeting Nectin-4 revolutionized the treatment of metastatic BCA. However, BCA exhibits diverse histological subtypes with varying prognoses, and the prevalence of Nectin-4 expression remained unclear. Rodler et al.  focused CD155 is mainly expressed in various cancer cells. Mori et al.  studied Gemcitabine is a commonly used chemotherapy drug, but resistance often limits its effectiveness. Wang et al.  investigRNA-binding proteins play an essential role in post-transcriptional gene regulation, and their dysregulation has been implicated in cancer. Gu et al.  developeFerroptosis, a form of regulated cell death, has emerged as a potential therapeutic target in various cancers. Zhang et al.  exploredImmunotherapy has shown promise in the treatment of BCA, but response rates can vary. Shimizu et al.  investigRadical prostatectomy is a common treatment option for localized prostate cancer, and it is crucial to consider not only the surgical procedure itself but also the supportive measures provided to patients. Wolf et al.  aimed toIn conclusion, the collection of articles in the Special Issue “Insights into Urologic Cancer” has made substantial contributions to our comprehension of urological malignancies. These studies have shed light on various aspects of urological cancers. The studies have also shed light on emerging therapeutic approaches, such as targeting specific molecular pathways or exploring the role of circular RNAs in overcoming drug resistance.Looking ahead, the insights gained from these studies open up new avenues for future functional, translational, and clinical research. Further investigations can build upon the knowledge obtained in this Special Issue to refine diagnostic methods, optimize treatment protocols, and develop novel therapeutic interventions. By addressing the gaps in our understanding of urological malignancies, future research endeavors hold the potential to improve patient outcomes and to ultimately contribute to the global fight against urologic cancers.


Depending on the state of its raw materials, final products, and processes, materials manufacturing can be classified into either top-down manufacturing and bottom-up manufacturing, or subtractive manufacturing (SM) and additive manufacturing (AM). Some important top-down manufacturing methods include casting , welding2O3, using a laser cladding process. Yin et al. [−1 and dynamic tensile deformation behaviors with a wide strain rate range, varying from 33 to 600 s−1. Zhang et al. [Hedhibi et al.  studied n et al.  studied g et al.  investigg et al.  investigChen et al.  studied The variety and quality of all these papers are addressed to both academic and industrial researchers who are looking for new information that can contribute to the advancement of future research in these highly challenging fields. It is our hope, as guest editors, that you find this volume interesting. We would like to express our sincere gratitude to the authors for their contributions and cooperation during the editorial process. We are indebted to the reviewers for their constructive suggestions and comments. We thank the editorial team for their strong support throughout the entire process.


Gastrodiscoides hominis. Both parasitic infections are important intestinal food-borne diseases. Humans become infected after ingestion of raw or insufficiently cooked molluscs, fish, crustaceans, amphibians or aquatic vegetables. Thus, eating habits are essential to determine the distribution of these parasitic diseases and, traditionally, they have been considered as minor diseases confined to low-income areas, mainly in Asia. However, this scenario is changing and the population at risk are currently expanding in relation to factors such as new eating habits in developed countries, growing international markets, improved transportation systems and demographic changes. These aspects determine the necessity of a better understanding of these parasitic diseases. Herein, we review the main features of human echinostomiasis and gastrodiscoidiasis in relation to their biology, epidemiology, immunology, clinical aspects, diagnosis and treatment.In the present paper, we review two of the most neglected intestinal food-borne trematodiases: echinostomiasis, caused by members of the family Echinostomatidae, and gastrodiscoidiasis produced by the amphistome  Over 100 species of digenetic trematodes have been reported infecting humans, many of them transmitted through food. Food-borne trematodiases constitute one of the most neglected tropical diseases group and includes liver flukes, lung flukes and intestinal flukes. Commonly, these parasitic infections have been ignored both in terms of research funding and presence in the public media. More than 40 million people are currently infected and about 10% of the world's population live at risk of infection  by cystoscopy. The patient complained of haematuria and dysuria but he did not show intestinal symptoms. The authors suggested that the metacercariae could penetrate through the intestinal wall into the urinary bladder, where the parasite attained maturity.Strikingly, Miao et al.  recentlyet al., et al. . In fact, most recent reviews differ in the number of species causing this parasitic disease. Toledo and Esteban  harbouring the infective metacercariae  (50 000 people infected), Echinochasmus japonicus (about 5000 cases) and Echinostoma cinetorchis and Acanthoparyphium tyosenense (with about 1000 cases each). This evidences the need for systematic epidemiological surveys, especially in areas where consumption of raw or undercooked intermediate hosts of echinostomes is a common habit.The current incidence of human echinostomiasis is not known. Most of the available information is based on sporadic reports with scarce information and, in many cases, lacking specific identification as mentioned above. Moreover, microscopists may misinterpret echinostome eggs, particularly considering that eggs of different echinostome species markedly resemble making difficult specific diagnosis  coexist with the human practice of eating undercooked intermediate hosts  from lakes. An average prevalence of 43%, but attaining 96%, of Echinostoma lindoense was reported from 1937 to 1956 in residents in the lake Lindu Valley (Sulawesi) . Infections were related to the local habit of eating raw bivalves  has been described on the basis of adult flukes collected from Riparian people residing along the Mekong river. Parasites were detected in six Riparian people from the localities of Kratie and Takeo  and/or IL-13 , 297 white blood cells per μL  and a positive result of 2+ for occult blood in the urine. Moreover, haematuria was accompanied by urgency and dysuria (Miao et al., In ectopic locations such as the urinary bladder, infection was characterized by haematuria with 305 red blood cells per μm × 43–90 μm (Esteban et al., Opisthorchis viverrini (Crellen et al., et al., et al., Laboratory diagnosis of echinostomiasis is based on the finding of eggs in feces. The eggs are yellow-brown and thin-shelled with an operculum, and a slight thickening of the shell at the abopercular end. They are unembryonated when passed in feces. The size of human-infecting echinostome eggs ranges 66–145 −1 of praziquantel is recommended for treatment of intestinal fluke infections. Echinostome infections can be treated successfully with slightly lower – single, oral 10–20 mg kg−1 praziquantel (Chai et al., Praziquantel is the drug of choice for intestinal fluke infections although it is not included in the US product labelling for these infections. A single dose of 25 mg kgG. hominis. Adult worms are pyramidal in shape and measure 8–14 × 5.5–7.5 mm2 (Mas-Coma et al., G. hominis include a subterminal pharynx, tandem, lobed testes, a post-testicular ovary, an ascending uterus and a ventral genital pore (Mas-Coma et al., Gastrodiscoidiasis is a plant-borne parasitic disease caused by the intestinal amphistome G. hominis is not well known (et al., et al., Helicorbis coenosus is known to act as the first intermediate host (Mas-Coma et al., et al., et al., et al., et al., Life cycle of ll known . Adult fll known . Pigs apll known , but it et al., et al., et al., G. hominis is not a common parasite of humans, high prevalences have been found in some areas, especially in India. Buckley (First cases of human gastrodiscoidiasis were reported in India. Thereafter, human cases have been found in Burma, Nepal, Pakistan, Myanmar, Vietnam, the Philippines, Thailand, China, Kazakhstan, Indian immigrants in Guyana, Zambia, Nigeria and the Volga Delta in Russia (Yu and Mott,  Buckley  reported Buckley .et al., et al. (G. hominis. Moreover, infection with metacercariae encysted in animal products, such as raw or undercooked crustaceans, molluscs or amphibians also may occur (Fried et al., Most of the cases appear to be related to the consumption of tainted vegetables directly collected from ponds and rivers, which is a common practice in some Asian countries (Sah , et al.  analysedet al., et al., et al., et al., Human gastrodiscoidiasis is commonly asymptomatic. In heavy infections, epigastric pain, abdominal discomfort, diarrhoea and headache may occur (Toledo 2 (et al., et al., et al., et al., Et al., Diagnosis of human gastrodiscoidiasis is performed by detection of eggs in feces. The egg is operculated, non-embryonated and measuring about 150 × 70 mm2  (Mas-ComHuman echinostomiasis and gastrodiscoidiasis are among the most neglected intestinal trematode infections. Both parasite infections have been considered as minor diseases mainly confined to some areas of Asia. However, the real prevalence of these infections is not known, which makes necessary further efforts and systematic helminthological surveys to determine the real impact on human health. This is of particular importance considering that several factors such as growing international markets, new eating habits in developed countries or demographic changes may be expanding their risk of infection and prevalence in areas where these diseases were not known. Thus, further studies are required to elaborate new maps of risk and a more detailed follow-up may be useful to gain a better understanding of the current incidence of these diseases.


Robust Perfect Adaptation (RPA), or robust homeostasis, is a ubiquitous property of biological systems, and ensures that key properties of the system can reset themselves in response to environmental disturbances, and maintain a fixed value (the system’s ‘setpoint’) at steady-state. RPA is a structural property of biological networks, and is independent of special parameter choices–hence, ‘robust’. Simple network configurations that can support RPA have been known for several decades –3, but u7, encompassing single-input/single output-networks subjected to constant-in-time disturbances, under the assumption of stability.Over the past several years, we have provided definitive answers to this question –6–both aPLOS Computational Biology recently published an article by Bhattacharya et al. [a et al.  which cla et al.  in the ca et al. . We alsoPLOS Computational Biology that all RPA-capable networks–regardless of size or complexity–are necessarily modular in nature. Large and highly complex RPA-capable networks may be decomposable into many such ‘basis modules’, which can admit rich and complex realizations, but which can only be drawn from two distinct and well-characterized classes: Opposer modules and Balancer modules. Particularly simple RPA-capable networks, such as the three-node networks discovered by Ma et al. [First and foremost, we acknowledge that the Bhattacharya et al. article  developsa et al.  by compua et al.  misreprea et al.  article a et al.  we by noa et al. , 9. Beloopposer nodes; all other nodes in a network are characterized by non-zero kinetic multipliers. In our paper [opposing sets (Theorem 3 in [without an opposer node) embedded into the route segments of the module . We alsur paper ). We devrem 3 in ), accounContrary to the claims of the Bhattacharya et al.  paper, tmust be a negative feedback loop. This more precise statement encompasses more complex versions of Opposer modules that include opposing sets; it also allows for the possibility that other  feedback loops -th order polynomial of up to (n−1)! terms for an n-node network) as points in a topological space, together with collections of ‘independently-adapting subsets’. This collection of subsets constitutes a topology on the terms of the RPA equation. We proved that a ‘minimal’ such subset could belong to one of two distinct forms: S-sets and M-sets. Only through a comprehensive analysis of the permissible algebraic structures of these two classes of subsets, and by considering the relationship of the contents of these subsets to structural properties of the associated network, could a topological basis for any RPA equation be definitively established. And only by relating these topological basis sets to their corresponding network architectures (modules), could we arrive at an exhaustive description of all possible RPA-capable network designs. In doing so, we identified novel network features of RPA-promoting modules, such as opposing sets (see 4–7 for further details), and also rigorously established the intermodular connectivity rules that allow arbitrarily large networks to achieve RPA through multi-modular network designs.The overarching technical difficulty with the Bhattacharya et al.  study isopposing sets), while point (2) represents a simplified description of an M-set. In this connection, we clarify for the readers of PLOS Computational Biology that the network designs considered by Bhattacharya et al. [Interestingly, Bhattacharya et al.  claim ina et al. , which ta et al. , and ignmay contain embedded feedback loops comprised entirely of balancer nodes (not opposer nodes); these feedback loops are compatible with RPA, but not required. Their Theorem 3 [Many results and special cases have been ‘rediscovered’ and presented as ‘new’ by Bhattacharya et al. , despiteheorem 3  also faiheorem 3  follows heorem 3  follows While we recognize that Bhattacharya et al.  identifyPLOS Computational Biology to consider the fundamental network principles governing more complex phenotypes–Turing patterning, for instance, or multistability/switching responses. These grand challenges remain open.As we note in a more recent study , the que


Dear Editor,The recent article by Radaelli et al.  presentsRadaelli et al.  then posThe simple answer is that loss of power does not yet have a name.Sarcopenia is generally considered a loss of muscle mass. A quick literature search revealed the first four mentions of sarcopenia in 1993  are famous for responding to identified diseases… A new, well publicized disorder… might stimulate a… public response" [In 1993, Dr. Butler, the editor-in-chief of the journal esponse" .potentiapenia.As long as 30 years ago, in 1993, Rogers and Evans  mentione


An age-at-death estimation method using the first rib may be particularly advantageous as this rib is relatively easy to identify, not easily damaged postmortem, and associated with less mechanical stresses compared to other age indicators. Previously, mixed results have been achieved using the first rib to estimate age-at-death. This study aimed to develop and test an age-at-death estimation method using the first rib. An identified modern black South African sample of 260 skeletons were used to collect age-related data from the first rib. Multiple linear regression analysis equations were created from this data for male, female, and combined samples. When tested on a hold-out sample, equations generated mean inaccuracies of 7–13 years for point estimates. The 95% confidence intervals contained the true age in 11–33% of individuals depending on the equation used, but wider intervals generated using 95% prediction intervals contained true ages for 100% of individuals. Point estimate inaccuracies are comparable to other age-at-death estimation methods and may be useful if single indicator estimation is unavoidable in the case of missing or damaged bones. However, combined methods that use indicators from many areas of the skeleton are preferable and may reduce interval widths. Adult age-at-death estimation from the skeleton is difficult because of inherent human variation as people age. Different statistical approaches and observer subjectivity add to the complexity of obtaining a reliable age estimate from the skeleton –5. For tKunos et al.  were theThese authors concluded that the overall age-at-death distribution pattern between observers (intra- and interobserver agreement) and also between the estimated and known age distributions were not statistically significantly different. As both these distribution patterns are calculated using the mean differences between observations, these reported averages could mask large individual differences. Kunos et al. note this by stating that individual specimen’s ages could markedly differ between observations and also between estimated and known ages . Overalln = 29) of the Kunos et al. [n = 39) found that ages of only 55% of skeletons were correctly identified, and in contrast found that the over 60-year-old age group was misclassified most often, through underestimation [A small independent validation  of presumptively or positively identified males from single internment graves in Kosovo. They modified the Kunos et al. [As advanced mathematical techniques have become increasingly popular to analyze known biological age-at-death indicators, the relationship between age and the first rib was also developed into a Bayesian analysis method . DiGangis et al.  method ss et al.  found thn = 470) sample of convenience that contained only males. Thus, Merrit [n = 20) of male individuals from European ancestry to compare the performance of, among other methods, the Kunos et al. [Merrit  noticed , Merrit  used a ss et al.  and DiGas et al.  methods s et al. . Unfortus et al.  point ess et al.  point ess et al.  not onlys et al.  method ts et al. , but thes et al. , Lovejoys et al. , Todd [1s et al. , and Bros et al. ). In cons et al.  method ws et al. , 17, Pass et al. , Buckbers et al. , and Rous et al.  method ws et al.  method , CF2 , and CF3  were statistically significantly higher for males compared to females. This significant difference might be indicative of unique patterns of aging due to lifestyle differences and suggested that functions of prediction should be adapted to consider sex.A Mann–Whitney Initial results for multiple linear regression containing all features  showed a 69% correlation with age using the combined sample and 64% and 75% for the female and male subgroups, respectively. However, all five features did not contribute statistically significantly to the multifactorial regression equation. Thus, the features with a low impact on the equation were manually excluded to produce the final equations in Table r = 68%), but using the combined sex equation produced higher correlations than the female equation (r = 66% compared to r = 63%). Only between 39 and 47% (r2) of age variability is accounted for by the independent variables . Unfortunately, the equation for the female subgroup performs particularly poorly (low r2 and accuracy). One explanation for the poor accuracy of the female group could be the underlying relationships between skeletal aging and female sex hormones or pregnancy. Any such female-specific confounders could be poorly accounted for due to the original all-male sample used for category description development. Thus, revisiting category descriptions for female samples may be advisable.One factor that clearly influences the relationship between the structural changes of the first rib and age, in the current study, is sex. This could be an unintentional effect introduced by the category descriptions of DiGangi et al. , which wAlthough some of the out-of-sample validation results were disappointing, many of these results are comparable to previous studies. Not only are the mean inaccuracies for the point estimates of the current study (13, 7, and 9 years for female, male, and pooled, Table In conclusion, the first rib contains some age-related information that can be used to make predictions related to age-at-death but should ideally be used in combination with other features from the skeleton. It performed better in males than in females. This study once again demonstrates the difficulties with adult age estimation, with narrow, accurate estimates using macroscopic features still remaining elusive.


A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was ‘in patients undergoing mitral valve surgery, does atrial incision affect early postoperative rates of atrial arrhythmia’. Two hundred and four papers were found. Nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Data suggest that a transeptal incision is associated with increased rates of postoperative atrial arrhythmia compared with direct left atriotomy. A best evidence topic was constructed according to a structured protocol. A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS .In [patients undergoing mitral valve surgery] does [atrial incision] affect [postoperative rates of atrial arrhythmia].A 56-year-old male presents for mitral valve (MV) surgery with severe mitral regurgitation from ‘posterior leaflet’ prolapse. His left atrium is mildly dilated on transthoracic echocardiogram. He is in sinus rhythm (SR) with no history of atrial fibrillation (AF). Will the atrial incision affect the risk of early postoperative atrial arrhythmia (AA)?Medline 1950 to 2020 using Ovid interface:[cardiac surgical procedures/OR heart atria/su [surgery] OR mitral valve insufficiency/su [surgery]]AND  OR electrocardiography/OR postoperative complications/OR tachycardia, ectopic atrial/ep, et ]AND [incision.mp OR trans$eptal.mp OR sondergaard$.mp OR interatrial groove.mp OR waterston$.mp OR superior trans$eptal.mp]Two hundred and four papers were found using the reported search. From these 9 papers were identified that provided the best evidence to answer the question. These are presented in Table et al. [Utley et al.  prospectet al. [n = 25) and superior transeptal (n = 65) approaches. Three patients in the left atriotomy group developed a junctional rhythm, all which resolved on discharge. Twenty-five patients in the superior transeptal group developed a junctional rhythm, 3 remained in a junctional rhythm at 6 weeks. Again, the authors purported the advantages in view and visualization via the superior transeptal approach, however, as seen with in Utely et al., rates of repair were actually lower in the superior transeptal group when compared to the atriotomy group. There was no mention of underlying aetiology of valve dysfunction to further comment.Kumar et al.  studied et al. [Bernstein et al.  studied et al. [A retrospective study performed by Masuda et al.  in 1996 et al. [n = 54) and left atriotomy (n = 22). They reported follow-up to 2 years. Nineteen patients in the superior transeptal group were in SR preoperatively. Of this group, 2 patients developed persistent longstanding postoperative AF. Seven patients in the left atriotomy group were in SR preoperatively with one patient developing a junctional rhythm requiring PPM. No patient remained in AF at 2 years. Takeshita et al. also performed preoperative and postoperative coronary angiograms on 9 patients undergoing superior transeptal approach during this study. In all 9 cases the SA nodal artery had been divided by the superior transeptal approach; however, nodal function ‘was not severely impaired’.Takeshita et al.  studied et al. [et al. reported no difference in rates of AA, including AF and junctional rhythms. They suggested preoperative factors such as left atrial (LA) dilatation, increased LA pressures and chronicity of mitral disease are more contributive to rates of postoperative rhythm disturbances than incision used. They did not differentiate between AFl and AF.Gaudino et al.  set out et al. [et al. also assessed sinus nodal artery courses preoperatively in the superior transeptal group and found no clear correlation between course and postoperative sinus node dysfunction. They did demonstrate much higher rates of repair in the superior septal group than the other 2 incisions.Tenpaku et al.  comparedNienaber and Glower  retrospeet al. [Lukac et al.  performe. Interestingly, although the vast majority of papers purport the advantage of the transeptal and superior transeptal approaches in regard to superior view of the MV, rates of repair via this superior incision were not reflected in all studies. Overall, the risk of re-entrant AAs needs to be weighed against the advantages of access to the MV achieved via transeptal approaches to the left atrium.There remains a paucity of data looking at rates of AAs  in relation to different access incisions in MV surgery. The majority of the studies are of low volume and difficult to directly compare due to differing study designs and outcome measures. The available data suggest that there is a higher risk of AAs when a transeptal approach (either superior or limited) is taken compared with a direct LA approach. It is felt that right atrial tachyarrhythmias are usually a result of the incision resulting in a proarrhythmogenic nidus whilst left AAs are due to the underlying pathologyConflict of interest: none declared.


Eye tracking has the potential to characterize autism at a unique intermediate level, with links ‘down’ to underlying neurocognitive networks, as well as ‘up’ to everyday function and dysfunction. Because it is non-invasive and does not require advanced motor responses or language, eye tracking is particularly important for the study of young children and infants. In this article, we review eye tracking studies of young children with autism spectrum disorder (ASD) and children at risk for ASD. Reduced looking time at people and faces, as well as problems with disengagement of attention, appear to be among the earliest signs of ASD, emerging during the first year of life. In toddlers with ASD, altered looking patterns across facial parts such as the eyes and mouth have been found, together with limited orienting to biological motion. We provide a detailed discussion of these and other key findings and highlight methodological opportunities and challenges for eye tracking research of young children with ASD. We conclude that eye tracking can reveal important features of the complex picture of autism. Autism spectrum disorder (ASD) is a neurodevelopmental condition defined by impairments across the areas of reciprocal social interaction and verbal and non-verbal communication, alongside repetitive and stereotyped behaviors . InterveUnderstanding how infants and children use their eyes in various contexts is important to understanding their opportunities for learning and development -16. An eCorneal reflection eye tracking is the most common method used to study gaze performance in infants and young children ,21. ThisIn this review, we critically assess the use of eye tracking in research focused on autism early in life. Eye tracking studies were identified through searches (through August 2013) in PubMed, Web of Science, and Google Scholar using ‘autism’ , ‘child’ , and ‘eye tracking’ as keywords ’ and that ‘the combination of a preference for geometry combined with saccade quantity might be a particularly strong early identifier of autism’ (pp. 107–108). However, this suggestion remains speculative given that no data were presented to support the view that the looking time measure and the saccade frequency measure (fixation rate) reflected independent processes. Alternatively, interest in a particular type of object increases the fixation length on that object (and thus decreases the fixation rate), leading to more aggregated looking time at that object as well.The Pierce l. study  may serv [et al.  reportedet al. [In the context of this review, it is worth noting that the paired visual preference paradigm does not require eye tracking technology. For example, a non–eye tracking study by Tek et al.  used theEvent-related designs typically focus on properties of gaze shifts , and the paradigms included in this section have a more experimental flavor than the (semi-) naturalistic approaches.et al. [Using an event-related paradigm called the gap overlap task, Elison et al.  investigWhile Elison studied saccadic reaction times, Falck-Ytter  used eyeet al. [et al. [et al. [et al. [et al. [et al. [Yet another event-related paradigm of particular relevance for autism research is the gaze following task. Bedford et al.  used a s [et al.  and Youn [et al.  to map g [et al.  and show [et al. , but ind [et al. , who rep [et al.  found th [et al.  suggeste [et al. .The studies reviewed in this section illustrate the value of event-related eye tracking measures for understanding aspects of oculomotor performance, visual orienting, action prediction and gaze following.et al. point to the possibility that basic attentional functions are already impaired in ASD during the first year of life. This conclusion is also supported by Elsabbagh et al. , altet al. [et al. [et al., who used static cues, Elsabbagh et al. used a dynamic central cue . Another important difference was that Elsabbagh et al. [et al. [et al. used corneal reflection eye tracking, Elsabbagh et al. extracted latencies from video recordings of eye movements. Finally, Elsabbagh et al. used non-social stimuli, while Elison used mixed social and non-social stimuli. Interestingly, in a study of toddlers, Chawarska et al. [The studies by Elison et al.  and Elsa [et al. ,92 had sh et al. ,92 inclu [et al.  based th [et al. . Furthera et al.  found noet al. [In light of these findings and because studies of ASD are orienting toward younger populations, it may be useful to briefly review some basic findings related to the typically developing oculomotor system . At biret al. . These ret al. . As infaet al. ,98. Arouet al. . This tret al. . The halet al. . Evidencet al. ,103, andet al. . Saccadeet al. . Thus, eet al. also illustrates how eye tracking and brain-based measures can be linked, which clearly is a priority for future research. Although plausible neural mechanisms for some eye tracking measures have been established [et al. [The study by Elison ablished  , thablished . Key andablished  reported [et al.  suggeste [et al. . The ‘fa [et al. . Process [et al. ,110,111, [et al. . Finally [et al. , but the [et al. ,113.This review has covered eye tracking studies of early autism, ranging from research that involved viewing of naturalistic scenes to highly experimental designs. We have argued that future research can benefit from taking more advantage of the unique options provided by eye tracking ,53,57. SWhat are the substantial findings from this body of research? Several of the reviewed studies have found that reduced looking time to people and faces is characteristic of young infants and toddlers with ASD ,32,34,35This review also covers some controversies. One concerns how young children with ASD look at faces, in particular their looking time to other people’s eyes and mouths. The reviewed studies indicate that looking time to eyes and mouth probably depends on a number of contextual and participant factors (diagnostic status being only one of many) that are currently relatively poorly understood. However, it now seems fair to conclude that looking time to the mouth is related to language function at specific early periods in typical development ,58. AnotFor researchers not familiar with eye tracking, it can be difficult to realize the diversity of the questions the method can address. In fact, a full overview of the possibilities associated with it is outside the scope of this article . The spaIn sum, although eye tracking has some drawbacks (primarily high cost and expertise requirements), there is a great potential to exploit and develop this method further in the field of early autism. Eye tracking data can be conceptualized as describing autism at a unique, intermediate level, with links ‘down’ to underlying neurocognitive networks, as well as ‘up’ to everyday function and dysfunction. By describing these links in detail, eye tracking will reveal important features of the complex picture of autism.Written informed consent was obtained from the children's guardian/parent/next of kin for the publication of this report and any accompanying images.ADOS: Autism diagnostic observation schedule; AOI: Area of interest; ASD: Aautism spectrum disorder; ERP: Event-related potential; SLL: Specific language disorder.The authors declare that they have no competing interests.TFY wrote the paper with contributions from SB and GG. All authors read and approved the final manuscript.List of identified eye tracking studies.Click here for file


Understanding the structure of interphase chromosomes is essential to elucidate regulatory mechanisms of gene expression. During recent years, high-throughput DNA sequencing expanded the power of chromosome conformation capture (3C) methods that provide information about reciprocal spatial proximity of chromosomal loci. Since 2012, it is known that entire chromatin in interphase chromosomes is organized into regions with strongly increased frequency of internal contacts. These regions, with the average size of ∼1 Mb, were named topological domains. More recent studies demonstrated presence of unconstrained supercoiling in interphase chromosomes. Using Brownian dynamics simulations, we show here that by including supercoiling into models of topological domains one can reproduce and thus provide possible explanations of several experimentally observed characteristics of interphase chromosomes, such as their complex contact maps. Such linkers do not force the two ends of a given topological domains to stay together but rather let them to fluctuate around positions dictated by supercoiling of modelled topological domains. A similar behaviour would be expected for supercoiled topological domains where boundary elements are attached to different nuclear granules. Importantly, the linker chains serve only an accessory role and are not entered into the statistics of contacts. Using the model described earlier in the text, we checked whether supercoiling can cause formation of topological domains, i.e. regions with 2- to 3-fold increased frequency of contacts as compared with loci with similar genomic distance but located in different topological domains . The larger loops thus correspond to ∼800 000 bp and are close to the average size of topological domains . This later result agrees with the notion that supercoiling in topological domains is dynamic and may change with cell activity .To evaluate the effect of supercoiling in a more quantitative way, we compared how the average contact probability decreases with the separating genomic distance in simulations and in experiments. As experimental data, we took first intra- and inter-domain contact probabilities involving topological domains E, F and H in the X-chromosome inactivation centre of mouse embryonic stem cells that were presented in et al. . As showet al. . It is i . It is important to mention here that the scale of our large chromosome fragment model is effectively set by the average number of beads used to model individual topological domains, which in reality have the average size of ∼1 Mb. et al. (et al. (et al. (Simulation results presented up to now were obtained using a model where the diameter of beads corresponds to the diameter of 30-nm chromatin fibres. Taking the linear density of 30-nm chromatin fibres , one can. et al. . To have. et al. . It is v. et al. A. A simi (et al.  (see Fig (et al. A. Howeve (et al. A. It is  (et al.  also, re (et al. ,30. Howe (et al. . If that (et al. ,29. With (et al. ,29.Figuet al. involved specific binders that only aggregate together chromatin portions belonging to the same topological domain. That model is able to imitate general characteristics of topological domains, but it requires that each topological domain should have domain-specific binders recognizing it. Because there are several thousands of topological domains in genomes of higher eukaryotes, one would also need to have several thousand species of these specific binders. In addition, each topological domain would need to have highly specific markers enabling it to attract its specific binders. Barbieri et al. did not propose, what could be these specific markers and specific binders for each topological domain.We have presented a relatively simple model of organization of topological domains that agrees with the available 3C data. It is important though to discuss how our model compares with other models in the literature. Because the discovery of topological domains in eukaryotic chromosomes is relatively recent, only few papers discussed their possible structure ,31, and Several earlier papers, preceding the discovery of topological domains, proposed models where chromosomes are organized into sequentially arranged closed loops ,33. We set al. (When this article was under review, a new study was published that combined high resolution 3C data and polymer modelling to elucidate the structure of bacterial chromosomes . It was et al.  suggesteSupplementary Data are available at NAR Online.Swiss National Science Foundation grant [31003A_138267 to A.S.]. Funding for open access charge: Waived by Oxford University Press. Conflict of interest statement. None declared.


We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities , other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children. Leo Kanner described autism in 1943 in 11 children manifesting withdrawal from human contact as early as age 1 year postulating origins in prenatal life . SeveralSymptoms of ASD usually begin in early childhood with evidence of delayed development before age 3 years. The American Academy of Pediatrics recommends autism screening for early identification and intervention by at least age 12 months and again at 24 months. Rating scales helpful in establishing the diagnosis are Autism Diagnostic Interview- Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) in combination with clinical presentation , 6. The etiology of ASD is complex and encompasses the roles of genes, the environment (epigenetics) and the mitochondria. Mitochondria are cellular organelles that function to control energy production necessary for brain development and activity. Researchers are increasingly identifying mitochondrial abnormalities in young children with ASD since the most severe cases present early with features of ASD. Better awareness and more accurate and detailed genetic and biochemical testing are now available for the younger patient presenting with developmental delay or behavioral problems. et al. [Epidemiologic and family studies suggest that genetic risk factors are present. Monogenic causes are identifiable in less than 20 percent of subjects with ASD. The remaining subjects have other genetic or multigenic causes and/or epigenetic influences which are environmental factors altering gene expression without changing the DNA sequence -10. Epiget al. . The recde novo changes in genes are unlikely to occur so quickly. Specific genetic and cytogenetic conditions associated with ASD are summarized in a recent review [Fragile X syndrome and tuberous sclerosis are the most common single gene conditions associated with ASD. The commonest chromosomal abnormality in non-syndromal autism is duplication of the 15q11-q13 region, accounting for 5% of patients with autism. Large microdeletions in chromosome 16p11.2 and 22q regions account for another 1% of cases . The rapet al. [MECP2 gene defects in females), 3% with PTEN gene mutations in those with a head circumference > 2.5 SD, approximately 10% with other genetic syndromes  and 10% with small deletions or duplications identified using chromosomal microarrays.The role and importance of genetic testing for individuals with ASD is well recognized  with varet al.  later foet al.  used a tHigh resolution chromosome analysis detects 3 to 5 megabase-sized abnormalities; however, new technology using DNA or chromosomal microarrays can identify abnormalities 100 times smaller. Therefore, microdeletions and duplications may now be identified with microarrays in individuals with ASD who previously had normal cytogenetic testing. Children with ASD show a higher prevalence of microdeletions and duplications, particularly involving chromosome regions 1q24.2, 3p26.2, 4q34.2, 6q24.3 and 7q35 including those with non-syndromal ASD . TherefoShen and coworkers  studied et al. [CDH10) and cadherin 9 (CDH9) genes. The latter two genes encode neuronal cell-adhesion molecules. These findings were replicated in two independent cohorts and demonstrate an association with susceptibility to ASD. Wang et al.  reportedet al. [Sebat et al.  studied STXBP5) and neuronal leucine rich repeat 1 (NLRR1) genes. Syntaxin 5 regulates synaptic transmission at the presynaptic cleft and is known to inhibit synapse formation. Syntaxin 1 protein is increased in those with high functioning autism. The role of NLRR1 at the synaptic level is unknown but is thought to be related to neuronal growth [As a result of research into nucleotide sequences, microdeletions and duplications in children with ASD can now be identified including syntaxin binding protein 5 , two important gene networks expressed in the central nervous system.An autism genome-wide copy number variation study reported by Glessner et al.  in a larNext generation DNA sequencing is currently underway, allowing for rapid and efficient detection of mutations at the nuclear and mitochondrial DNA (mtDNA) level in human investigations and becoming part of clinical workup. Heteroplasmy or the existence of multiple mtDNA types within cells of an individual, is detectable using standard molecular genetic techniques which focus on hypervariable regions of the mitochondrial genome. With high-throughput next generation sequencing of the complete human mtDNA, which is faster and more powerful, accurate detection of heteroplasmy can be made throughout the mitochondrial genome not just in the hypervariable regions located in the cytoplasm of the cell enabling the study of correlation with diseases. et al. [Recently, Li et al.  sequenceWith a significant percentage of children with autism presenting with metabolic abnormalities  and other biochemical disturbances, identification of mitochondrial disorders is critical for early treatment. Long standing mitochondrial dysfunction can lead to major health complications and damage. If identified early, mitochondrial disorders can be managed with improved longevity and quality of life. Medical intervention and therapies are now available to specifically target the biochemical defect in the mitochondria and to improve function and bioenergy utilization and diminish the neurological insults that would occur if left untreated. Inborn errors of metabolism may contribute to at least 5% of cases with ASD . Deficie1).Mitochondria are intracellular organelles in the cytoplasm known as the power houses of the cell. They play a crucial role in adenosine 5’-triphosphate (ATP) production through oxidative phosphorylation (OXPHOS). The latter process is carried out by the electron transport chain made up of Complex I (NADH: Ubiquinone oxidoreductase or dehydrogenase), Complex II (Succinate:Ubiquinone oxidoreductase), Complex III (Coenzyme Q:Cytochrome c reductase or cytochrome bc1 complex), and Complex IV (Cytochrome c oxidase) required to convert food sources to cellular energy. The electron transport system is situated in the inner membrane of the mitochondria and contains proteins encoded by both nuclear and mitochondrial DNA . About 1Human mitochondrial DNA (mtDNA) is a circular double stranded DNA molecule contained within the mitochondrion and inherited solely from the mother. The evolutionary antecedents are bacterial plasmids. Each mitochondrion contains 2-10 mtDNA copies organized into nucleoids . This or2). When a mutation arises in a cellular mtDNA, it creates a mixed intracellular population of mutant and normal molecules known as heteroplasmy. When a cell divides, it is a matter of chance whether the mutant mtDNAs will be partitioned into one daughter cell or another. Therefore, over time, the percentage of mutant mtDNAs in different cell lineages can drift toward either pure mutant or normal (homoplasmy), a process known as replicative segregation, which then impacts on cellular energy and human diseases [Mitochondria are dynamic organelles that fuse and produce fission by changing shapes and size throughout the life of the cell. Thus far, the mitochondria cannot yet be accurately quantified but mtDNA can be analyzed. In mammals, each double-stranded circular mtDNA molecule consists of 15,000-17,000 base pairs containing a total of 37 genes   is caused by T8993G heteroplasmic mtDNA mutations. When heteroplasmy is present in less than 10 percent of copies, NARP findings are usually absent. At 10-70 percent, adult onset NARP is present, and at 70-100 percent childhood Leigh syndrome occurs. Other examples of known mitochondrial diseases include Myoclonic Epilepsy with Ragged Red Fibers (MERRF) and the disorder known as Mitochondria Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) . In the mitochondria ATP production, free oxygen radicals and reactive oxygen species (ROS) are produced and then normally removed from the cells by anti-oxidant enzymes. When the production of ROS and free radicals exceeds the limit, oxidative stress occurs, that is, ROS combine with lipids, nucleic acids and proteins in the cells leading to cell death by apoptosis or necrosis . Since bet al. [et al. [Coleman and Blass in  were theet al.  reportedet al.  then pro [et al.  studied  [et al.  in two u1 for a summary of known mitochondrial and nuclear gene defects in ASD). Recently, Shoffner and colleagues  studied Early cases reported by Graf and colleagues  provide et al. [dGK and TK2. The sister had no depletion of the mtDNA or mutations in the two nuclear genes. However, they did have mtDNA depletion in the skeletal muscle at a 72% level. These findings highlight the importance of the A3243G mtDNA mutation in ASD and the investigators proposed that mutations or depletion of mtDNA should be investigated in other children presenting with ASD.In addition, Pons et al.  followedet al. [et al. [et al. [Oliveira et al.  reported [et al. , but no  [et al.  reportedet al. [et al. [An interesting study by Fillano et al.  further  [et al.  found thet al. [SLC23A12. This most important gene located on chromosome 21q31 encodes a calcium-binding carrier protein used by the mitochondria. It is involved in the exchange of the amino acid aspartate for glutamate in the inner membrane of the mitochondria for use in the electron transport chain. Ramoz et al. [SLC25A12 gene associated with ASD in their study of 411 families. This association was confirmed by Seguarado et al. [et al. [Studies reviewed by Smith et al.  linked nz et al.  identifio et al.  and by S [et al. .et al. [et al. [SLC23A12 gene in their families with autism. Also, Chien et al. [SLC23A12 gene.A recent study by Ezugha et al.  of a 12- [et al.  also stun et al.  studied (POLG1) which codes for mitochondrial DNA polymerase [Mitochondrial DNA replication and maintenance is regulated by enzymes which are proteins encoded by nuclear DNA genes . One suclymerase . This gedGUOK gene mutations and hepatic failure with reductions in activity of mitochondrial complexes I, II and IV. However, the enzyme activity for complex II, which is encoded by nuclear DNA, was normal in these patients. Furthermore, quantitative mtDNA analysis showed a reduced mtDNA/nuclear DNA ratio of 8-39% in liver specimens from seven of the children. Studies have examined the role of nuclear genes in causing depletion of the mtDNA genome and tissue specific conditions , 62. MandGK and TK2, encoded by the nuclear genome [et al. [dGK was mutated in patients with reduced mtDNA/nuclear DNA ratios. A similar study by Saada et al. [TK2 nuclear gene. These two studies further supported that nuclear genes are linked to mtDNA but more research is needed to determine their role in autism and for identification of mtDNA genetic defects, mutations or for the mtDNA depletion status associated with related nuclear genome defects.The main supply for dNTPs required for energy comes from the deoxynucleoside salvage pathway regulated by two mitochondrial enzymes r genome , 64. Hen [et al.  examineda et al.  in two oPOLG1) is an important polymerase enzyme responsible for mtDNA replication and base excision repair [POLG1 enzyme is located on chromosome band 15q25 [POLG1 gene. Studies have shown that mutations or disturbances of the POLG1 gene cause deletions of mtDNA genes. Additionally, autism is linked to defects of human chromosome 15q11-q13 region including inverted duplications found in about 5% of cases with autism [et al. [Polymerase gamma , juvenile spino-cerebellar ataxia-epilepsy syndrome (SCAE) and Alpers-Huttenlocher hepatopathic poliodystrophy. These encephalomyopathies are caused by abnormal nuclear mitochondrial intergenomic cross-talk linked to POLG1 gene mutations and to mtDNA deletions. This strong link between nuclear genes and the mtDNA genome is further supported by a prevalence of 2% of individuals in the general population carrying this nuclear gene defect [e defect . TK2, DGK, PLOG, TWINKLE, ANT1 and TP can cause deletions and depletions of mtDNA, their involvement and frequency in ASD requires further investigation.Another nuclear gene that can cause multiple mtDNA abnormalities including duplications, deletions and point mutations is thymidine phosphorylase (TP) , 73. TheFinally, oxidative stress and gene methylation (epigenetics) are both considered to play a role in producing ASD. Oxidative stress in brain cells due to genetic or environmental causes, leads to decreased methionine synthase activity . Methionet al. [Deth et al.  further et al. . MeCP2 pet al. [Oxidative stress is also known to cause deletions of the mtDNA genes in mice models . For exaet al.  indirectet al. [To further evaluate for mitochondrial dysfunction and mtDNA abnormalities, Giulivi et al.  recentlyIn summary, the role of the mitochondria and mitochondrial defects are discussed in relationship to ASD. Several studies have linked autism to defects in oxidative phosphorylation encoded by mtDNA along with interaction of nuclear genes. Individuals with the ASD phenotype clearly show genetic-based primary mitochondrial disease. Further studies with the latest genetic technology such as next generation sequencing, microarrays, bioinformatics and biochemical assays will be required to determine the prevalence and type of mitochondrial defects in ASD. Elucidation of molecular abnormalities resulting from mitochondrial or genetic defects in individuals with ASD may lead to better treatment options and outcomes.