Several efforts in basic and clinical research have been contributing to unveiling the genetics behind autism spectrum disorders (ASD). However, despite these advancements, many individuals diagnosed with ASD and related neuropsychiatric conditions have been genetically investigated without elucidative results. The enormous genetic complexity of ASD-related conditions makes it a significant challenge to achieve, with a growing number of genes (close to a thousand) involved, belonging to different molecular pathways and presenting distinct genetic variations. Next-generation sequencing (NGS) is the approach most used in genetic research related to ASD, identifying de novo mutation, which is closely related to more severe clinical phenotypes, especially when they affect constrained and loss-of-function intolerant genes. On the other hand, de novo mutation findings contribute to a small percentage of the ASD population, since most of the cases and genetic variants associated with neuropsychiatric conditions are inherited and phenotypes are results of additive polygenic models, which makes statistical efforts more difficult. As a result, NGS investigation can sound vainly or unsuccessful, and new mutations on genes already related with ASD are classified as variants of unknown significance (VUS), hampering their endorsement to a clinical phenotype. This review is focused on currently available strategies to clarify the impact of VUS and to describe the efforts to identify more pieces of evidence throughout clinical interpretation and genetic curation process. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (ND), usually identified during early childhood according to clinical criteria, comprising impairment of the social abilities and cognitive competence, as well as typical behavior including stereotypic movements. Despite the criteria used to categorize someone under ASD’s umbrella, it is well known that ASD is not homogeneous in terms of clinical signs and genetic aspect, being close to having one thousand genes already implicated , 2. ConsBased on the challenging efforts to better characterize the ASD genetic background, several studies concentrate their energies to investigate and correlate the genetic profile of different ASD individuals. These investigations allowed the determination that only a small proportion of ASD cases have a clear-signed mendelian genetic background, while most of the current cases are caused by a complex combination of polygenic additive effect, comprising an enigma in terms of how these genetic variations are combined to manifest the autistic phenotypes , 8. Due Current investigations, both in clinical routines and research, also involve the use of next-generation sequencing (NGS) technologies to extract and sequence the entire genome (whole genome sequencing—WGS) or exome (whole exome sequencing—WES) of ASD individuals. These approaches usually imply in the identification of several genetic modifications described as variants of unknown significance (VUS), which effectively represent mutations where the pathogenicity and the function of the gene involved is unclear, turning it into a critical issue since most patients remain without a genetic explanation for their condition , 11. ThuMost ASD and associated developmental delay cases are a genetical combination of inherited common and rare genetic variants. On the other hand, non-inherited genetic mutations are the most clinically relevant alterations with higher morbidity when affecting constrained genes associated with neurodevelopmental biology –18.During NGS analysis and interpretation, it is essential to consider all genes and molecular pathways involved in the early stages of neurodevelopment. As demonstrated in several groups, genes expressed during neurogenesis and involved pathways are the most critical genes affected in ASD etiology. Particular examples of genes that are well established to be associated with synaptic function include GRIN2B (glutamate receptor ionotropic NMDA type 2B) and SHANK3 (SH3 And Multiple Ankyrin Repeat Domains 3), and associated with chromatin regulation include CHD2 (Chromodomain Helicase DNA Binding Protein 2) and CHD8 (Chromodomain Helicase DNA Binding Protein 8) –21. ThesThe Diagnostic and Statistical Manual of Mental Disorders), patients who have been previously diagnosed with autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger’s syndrome were genetically analyzed for de novo mutations (DNMs). Even when only considering the most damaging sort of genetic variants, the results demonstrated that DSM-4 ASD subcategories share many more similarities than differences, considering genes, gene expression, and molecular pathways , predicts the possible impact of amino acid substitutions on the stability and function of human proteins using structural and comparative evolutionary considerations by annotating the mutation using distinct databases. The tool combined all information and used a prediction method that employs machine-learning classification to estimate the probability of the missense mutation being damaging .Other similar approaches were also developed to annotate and analyze variants, such as SnpEff, which predicts and classifies genetic variants accordingly, i.e., to a synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frameshifts . AnotherAnother tool, SIFT (Sorting Intolerant From Tolerant), predicts whether an amino acid substitution affects protein function. The tool can distinguish between functionally neutral and deleterious amino acid changes, which was previously validated on mutagenesis studies and human polymorphisms .Other computational tools like SIFT and PolyPhen are based on a combination of methods and are used in prioritizing changes that are likely to cause a loss of protein function. However, their low specificity requires further evidence to support or refute pathogenicity that should be sought before reporting novel missense changes .Recently, 23 distinct computational methods were analyzed to evaluate the performance measures using independent benchmark datasets correlated with disease-causing genetic variants . The anaAlthough several computational tools have been widely used to predict potentially deleterious DNMs, and the previous comparative analysis suggests that more rigorous analysis is necessary to distinguish pathogenic variants, and consequently can accelerate the better identification of deleterious variants.The elucidation of the genetics behind ASD has been contributing significantly to phenotype elucidation. The last decade produced a precious amount of valuable information, which had to be systematized in ASD genetic research and public databases. There are three public databases specialized in genetic variants associated with ASD. SFARI is currently the main source for curated data categorizing associated risk genes with different scores and storing several genetic variants described in the scientific literature . AutDb  and Auti®) is composed of a set of germline mutations correlated with human inherited diseases (http://denovo-db.gs.washington.edu), which provides standardization of annotation and improves accessibility for independent studies reported by the literature. This bank comprised more the 23 thousands of trios, and detailed information about variant information ; detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant  , the AutBased on databases generated from several research groups, it is possible to incorporate gene expression data from brain transcriptomes of psychiatric patients to gene pathways associated with ASD, in order to produce more robust evidences and valuable information, to curate and interpret respective VUS in routine NGS analysis , 57–59.Other critical features to analyze during gene curation and interpretation in ASD and neuropsychiatric conditions are genetic constraints, haploinsufficiency, evolutionary conservation and population frequency of genetic variants. Considering population frequency, when genetic variants are extremely rare or even never reported at current databases, such as gnomAD (The Genome Aggregation Database) , this isIt is also important to mention that more severe clinical conditions and comorbidities tend to carry a higher genetic burden with several additional hits, including CNVs or rare inherited genetic variants, which are most of the time identified as VUS in neurotypical individuals, but in a significantly lower number . AnotherLast, it is crucial to consider that even sophisticated strategies used to reclassify VUS are not enough for some inconclusive cases, due to multiple and complex genetic profiles recently discovered. Genetic alterations at noncoding regions correspond to a fraction of ASD patients with inconclusive test results. Recent researches identified the relevance of noncoding DNMs at promoter regions  and inheConsidering all these pieces of evidence, they corroborate with the idea that genetic variants associated with neurodevelopmental and psychiatric conditions have a significant impact on reproductive fitness, not only due to rarity and constraint, but also when multiple hits are observed . ASD is We state that all authors have read the paper and approved the data and the conclusions presented therein, and all authors have contributed to the present manuscript with equal effort.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Autoimmune encephalitis is a rare and debilitating disease. An important question in clinical neurology is what factors may be correlated with outcomes in autoimmune encephalitis. There is observational data describing statistical analyses on such variables, but there are no review articles that collaborate and interpret this information. This data in brief article represents the data collection for such a review .Herein we summarize clinical information from 44 research articles, in particular pertaining to outcomes and prognostic variables. Specifications tableValue of the data•This data provides a summary of relevant publications in the field, including antibody types, outcome measures, prognosis variables and the quality of this information•Clinicians seeking to examine research articles for particular prognosis variables or in certain antibody subtypes can review this data to answer these questions easily•This data provides summaries of demographics, typical symptomatology, rates of tumor association and routine investigation findings for key antibody types•Clinicians can see rates of good and poor outcomes with respect to antibody subtype and the outcome measure of interest1N-methyl-D-aspartate receptor), VGKC (voltage-gated potassium channel) or GABAb (γ-aminobutyric acid receptor B). Other important abbreviations include MRI (magnetic resonance imaging), CSF  and EEG . A glossary of terms is provided to aid the interpretation of the following data tables.The data provided here is a summary of information in research articles describing prognosis in autoimmune encephalitis. This data includes entirely clinical information, with a focus on outcomes and prognosis variables. All causes of autoimmune encephalitis were included in the search, but most of the included articles described cases with antibodies directed to one of the cell surface antigens; NMDAR , and classified based on the publication design. Where discrepancy was found, consensus agreement was reached. The articles were objectively assessed for quality, using the Newcastle-Ottawa Scale for cohort and case-control studies


To what degree is cultural multi-level selection responsible for the rise of environmentally transformative human behaviors? And vice versa? From the clearing of vegetation using fire to the emergence of agriculture and beyond, human societies have increasingly sustained themselves through practices that enhance environmental productivity through ecosystem engineering. At the same time, human societies have increased in scale and complexity from mobile bands of hunter-gatherers to telecoupled world systems. We propose that these long-term changes are coupled through positive feedbacks among social and environmental changes, coevolved primarily through selection acting at the group level and above, and that this can be tested by combining archeological evidence with mechanistic experiments using an agent-based virtual laboratory (ABVL) approach. A more robust understanding of whether and how cultural multi-level selection couples human social change with environmental transformation may help in addressing the long-term sustainability challenges of the Anthropocene. Humans, unlike any other species in Earth’s history, gained the capacity to transform an entire planet , and dependence on non-kin exchange relationships, which together mark us as Earth’s first ultrasocial species , and performed new administrative functions Trigger . New forArcheological, historical, and ethnographic evidence confirms that societal scales have increased in parallel with the intensity of sociocultural niche construction Fig. . The proLarger scale societies have larger populations, but are also characterized by greater accumulations of cultural, ecological, and material inheritances, including the cultural practices, individual and group specializations, social institutions, exchange relationships, technologies, domesticated species, altered environments, and built infrastructure that have enabled them to sustain larger populations in increasingly human-altered environments Ellis . In otheMultiple authors have proposed that societal scale and ecosystem engineering are coupled through a cyclic system of positive feedbacks: upscaling drives intensification and intensification drives upscaling Ellis . The claAnthroecology theory proposes that the long-term trend towards larger scale societies with increasingly intensive ecosystem engineering is the result of a runaway evolutionary process of sociocultural niche construction Ellis . RunawayRunaway cultural niche construction occurs when socially learned traits for ecosystem engineering cause environmental changes that select for additional cultural or genetic traits  and increasing levels of cooperation and exchange among specialist individuals and groups with different expertise . More productive strategies for ecosystem engineering, often requiring larger scales of cooperation among specialists, increase the production of food, fiber and other resources, which enable larger populations, increased per capita consumption, and most importantly, the production of surpluses that can be extracted for social exchange through trade and taxation. When ecosystem engineering increases land productivity, it can also release labor from food production, creating new opportunities for increasing levels of social specialization and hierarchical societal development that include urban populations far from sites of food production. Increasingly complex hierarchical societies have the social capacity to engage in increasingly productive ecosystem engineering, and by increasing ecosystem productivity, they create the conditions necessary for the further evolution of social complexity in support of increasing societal scales.The basic principles of runaway sociocultural niche construction can be expressed through four related hypotheses: (1) larger scale societies cannot sustain themselves without more intensive systems of food production, (2) more intensive food production systems are not possible without more specialized and increasingly cooperative societies, (3) neither can evolve independent of the other, and (4) positive feedbacks between societal upscaling and ecosystem engineering productivity can drive major, coupled, long-term increases in societal scale and environmental transformation. To test these hypotheses, it will be necessary to build a model capable of simulating human societal upscaling coupled with ecological system dynamics to simulate the intensification of ecosystem engineering across landscapes. Such a model must include selection processes acting on individual human agents and their cultural traits associated with ecosystem engineering, resource extraction, and exchange with other agents, both kin and non-kin, within and across social groups and societies. Similarly, such a model must be capable of generating emergent, self-organized social groups, selection among groups, and dynamic selection pressures on the cultural traits defining individual, within group, and across group behaviors. Finally, to close the positive feedback loop, ecological consequences of ecosystem engineering, including environmental degradation, productivity enhancement, and their interactions with environmental heterogeneity and stochasticity also need to be simulated. All of these processes would need to be modeled in such a way that social processes and selection at group and societal levels, and their capacities to enact increasingly productive niche construction regimes, could be turned on, turned off, or set to various levels, to test the roles and relative importance of each in producing runaway sociocultural niche construction over many generations across increasingly large and complex agent populations in plausible social–ecological scenarios.Taken together, the requirements of such a model are clearly daunting. Nevertheless, there are clear prospects for building models capable of testing the basic hypotheses of runaway sociocultural niche construction. One of these prospects is an agent-based virtual laboratory (ABVL) approach employing a ‘generative social science’ mode of inquiry focused on developing and testing general theory on social–ecological interactions; ‘growing’ human societies and their adaptations to and of their environments from the bottom-up Epstein . The ABVTo move forward with an ABVL approach, a number of challenges are clear. The first is the need to assemble suitably detailed and reliable long-term spatially explicit datasets of social–ecological change across regions to enable model parameterization and/or validation for hypothesis testing. While empirical reconstructions of long-term cultural, social and environmental change will always be incomplete, such datasets are increasingly available through the efforts of archeologists, geographers, environmental historians and other scholars Zeder . From a Efforts to develop ABMs to test theory on the mechanisms of social–ecological change are beginning to bear fruit (Waring et al. Even with these advances, combining rich representations of both sociocultural and ecological processes and simulating their evolutionary feedbacks and emergent dynamics in realistic simulated landscapes over long time periods in a form capable of testing anthroecology theory against empirical evidence remains a major challenge and direction for future work, as described by Magliocca and Ellis . Model dEven greater challenges stem from need to confront simulated processes themselves with empirical evidence at appropriate levels to ensure that these are realistically represented (i.e., structural validation; (Brown et al. Anthroecology theory proposes that human societies gained the capacity to transform a planet, without intending to, through a runaway evolutionary process of sociocultural niche construction which caused societal upscaling and niche construction intensity to increase together. If these trends continue into the future, the results would likely be no better than they have been in the past: the generation of ever larger-scale societies, with ever larger populations continuing to shift the Earth system towards a hotter, more polluted, less biodiverse and less wild state. While human populations appear to be leveling off as a result of increasing development and urbanization, and livelihoods and longevity continue to improve, billions more are expected no matter how rapidly growth rates are reduced (Bradshaw and Brook Archeological evidence confirms that larger scale societies and more intensive niche construction practices evolved in parallel, but cannot determine whether these are mechanistically coupled through positive feedbacks. Is it possible for the intensity of sociocultural niche construction to increase even faster than growth in populations and per capita environmental demands? In other words, can the environmental demands of human societies shrink while populations continue to grow? There is some evidence that this may have occurred at times in the past and is in fact occurring now, as global agricultural land use has generally been growing more slowly than populations in recent decades, increasing food available per capita FAO . Either Even for the conditions of the deep past, when societies were smaller and less complex, the development of experimental approaches fully capable of testing mechanistic hypotheses on runaway sociocultural niche construction remain at an early stage of development. Achieving this capacity for contemporary societies will require overcoming serious technical, theoretical and empirical challenges. Nevertheless, the ABVL approach has the potential to investigate key questions of sustainability science. Is human sociocultural evolution sustainable over the long term? How will sociocultural evolution shape future trajectories of social and environmental change? How can these evolutionary processes be guided towards better outcomes for both humanity and nonhuman nature? By developing experimental approaches capable of testing hypotheses on the evolution of societies and the sociocultural niche construction regimes that sustain them, critical knowledge may be gained towards understanding and influencing societal transformation of Earth towards more sustainable and desirable futures.


A 34-year-old male presented with retrosternal chest pain, fatigue, shortness of breath, and a history of a previous episode of myocarditis four years prior. He had elevated troponin T, normal skeletal muscle enzymes, and negative inflammatory markers. Cardiac magnetic resonance imaging (MRI) confirmed active myocarditis with extensive myocardial fibrosis and normal left ventricular ejection fraction (LVEF). His myocarditis symptoms resolved with steroids and anti-inflammatory treatment, but on closer questioning, he reported a vague history of long-standing calf discomfort associated with episodes of stiffness, fatigue, and flu-like symptoms. MRI of the lower legs consequently demonstrated active myositis in the calf muscles. Immunomodulatory therapy was commenced with good effect. The patient is undergoing regular follow-up in both cardiology and rheumatology outpatient departments. Repeated MRI of the legs showed significant interval improvement in his skeletal muscle myositis, and repeat cardiac MRI demonstrated the resolution of myocarditis along with persistent stable extensive myocardial fibrosis and preserved LVEF. The patient has returned to full-time work. The diagnosis of myocarditis remains challenging given the diverse nature of clinical presentations . The exaA 34-year-old male was admitted to the hospital with recurrent episodes of retrosternal chest pain, fatigue, and shortness of breath with an elevated troponin T. He had suffered an acute episode of myocarditis four years previously requiring hospital admission. He had no other relevant medical history and no family history of cardiac disease. He is a nonsmoker and consumed alcohol occasionally. Clinical examination was unremarkable and did not show any evidence of heart failure or systemic disease. ECG showed normal sinus rhythm without any ischemic changes, and chest X-ray showed no evidence of infection or heart failure. Routine blood tests including antinuclear antibody, creatinine kinase (CK), rheumatoid factor, and C-reactive protein were all within normal limits apart from an elevated cardiac troponin T with a peak value of 2700 ng/l (<14 ng/l). Further extensive inflammatory, viral, and autoimmune screening was carried out and found to be negative. Subsequent coronary angiogram showed normal coronary arteries, and transthoracic echocardiography demonstrated left ventricular ejection fraction (LVEF) >55% with trace mitral regurgitation. Cardiac magnetic resonance imaging (MRI) demonstrated extensive subepicardial and midwall late enhancement typical of myocarditis in the anterior, lateral, and inferior walls along with extensive fibrosis with normal LVEF .A short course of steroids and anti-inflammatory medication as an inpatient resulted in the resolution of his myocarditis symptoms. The troponin T level normalized and the patient was discharged with a plan to repeat cardiac MRI in six months. On follow-up as an outpatient, it was decided to refer the patient to rheumatology for an opinion regarding ongoing immunomodulatory therapy. At this juncture, the patient stated that he also had symptoms of stiffness and aching in his calf muscles for quite some time but he did not consider it to be relevant. Despite persistently normal skeletal muscle enzyme levels, an MRI of the lower legs was performed and this showed active myositis involving the gastrocnemius muscles bilaterally . As the We describe an elusive case of a young male with recurrent episodes of acute myocarditis presenting with chest pain and elevated troponin T. All biochemical, immune, and autoimmune tests were within normal limits. However, he described a long-standing and persistent history of calf aching and discomfort. Consequently, lower limb MRI revealed that the patient had active myositis of his gastrocnemius muscles. This unexpected finding demonstrated that this inflammatory myositis was not isolated to cardiac muscle and by definition was still active despite initial treatment. As this patient had already accrued significant myocardial scarring, the finding of active myositis demonstrated the need for more effective long-term immunomodulatory therapy in order to preserve cardiac function. Cardiac involvement in patients with skeletal myositis was first reported in 1899 . SubclinOur case is unique as there was no evidence from the history, clinical examination, or extensive laboratory investigations to indicate a specific aetiology of this man's myositis. Endomyocardial biopsy is the gold standard test for myocarditis; however, the clinical presentation in conjunction with the raised troponin level and a cardiac MRI demonstrating myocardial muscle oedema in keeping with myocarditis was considered sufficient to make a diagnosis without a myocardial biopsy, since such a procedure would be invasive and not without significant side effects. Consequently, the patient was noted to have calf muscle symptoms and MRI demonstrated skeletal muscle oedema in a distribution in keeping with skeletal muscle myositis. At this juncture, a skeletal muscle biopsy was proposed but the patient was not happy to consent to this procedure. However, in light of the history and clinical and MRI findings, it was considered reasonable to make a diagnosis of skeletal muscle myositis on a background of myocarditis and to treat the patient accordingly.The first-line treatment of idiopathic inflammatory myositis is a high dose of corticosteroids (60–100 mg), which should be tapered after 4–6 weeks according to response . Most paIn conclusion, we report a rare case of clinically significant cardiac and skeletal myositis whose cause is unclear. In patients with acute myocarditis, it is important to consider the possibility of an associated skeletal myositis when suggestive symptoms are present. MRI can be useful to establish the diagnosis particularly if laboratory tests are not conclusive. Further trials are needed to determine whether cardiac involvement is associated with certain types and subtypes of myositis or not.


Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents. In experimental studies NAC has been reported to protect against PD development . Antioxidant defenses in SN are relatively low, compared to other regions of CNS, due to low levels of GSH, particularly during the early stages of PD when extravesicular DA and its degradation products may act as a GSH depleting agents , to reduce ROS. Also, GSH detoxifies xenobiotics and maintains sulfhydryl proteins in a reduced state  can reduce the risk of developing PD (Asanuma et al. Parkinson’s disease can be delayed, or its consequences attenuated through regular safe physical activity. Recent scientific studies suggest a combination of aerobic activities, strength training from moderate to high intensity, as well as balance training, gait training, functional activities and exercises that require agility (Fisher et al. Physiotherapeutic treatment should be started as soon as the diagnosis is confirmed and is a good way to help stimulate movement and quality of life as it improves the strength, coordination, and amplitude of the movements, i.e., by reducing the otherwise inexorable imbalance characterizing the progressive disease, thereby preventing contractures and falls Ahlskog .Environmental factors including exposure to metals, pesticides and drugs account for the majority of cases of Parkinson´s disease. Excessive oxidative stress accentuated by iron accumulation and abnormal protein aggregation in the nigrostriatal region of the brain are primary events in the development of the disease that need to be addressed by preventive measures. Iron is a necessary cofactor for the enzyme tyrosine hydroxylase responsible for DA synthesis, and accumulation of Fe in the SN deteriorates the function of tyrosine hydroxylase. Metal binding substances e.g. Deferiprone mobilize Fe from the SN possibly providing prevention. Caffeine, niacin, nicotine and salbutamol also seem to protect against progression by similar mechanisms. Supplementation with NAC together with selenium for optimal glutathione synthesis is recommended to reduce oxidative damage to sensitive SN cells.


Patients who do not sufficiently adhere to their dosing regimens will, ultimately, do not get the full benefit of their medication. For example, if direct oral anticoagulants (DOAC) are not taken continuously, an intervention to improve adherence or maintain persistence will show direct effects on clinical outcomes. Usually, adherent patients are defined by taking ≥80% of their medication. The resulting binary adherence status from this threshold can as well be used for predictive classification. Thus, the threshold can determine the prediction model’s performance to identify patients at risk for poor adherence by this binary adherence status. In this perspective, we propose a plan for model development and performance considering the threshold’s role. Concerning development demands, we extracted predictors from a systematic literature search on DOAC adherence to be used as a core set of candidate predictors. Independently, we investigated how well a future model would technically have to perform by modeling drug intake and thromboembolic events based on a rivaroxaban pharmacokinetic-pharmacodynamic model. Using this simulation framework for different thresholds, we projected the impact of an imperfectly predicted adherence status on the event risk, and how imperfect sensitivity and specificity affect the cost balance if a supporting intervention was offered to patients classified as non-adherent. Our simulation results suggest applying a rather high threshold (90%) for discrimination between patients at low or high risk for non-adherence by a prediction model in order to assure cost-efficient implementation. Key advantages of direct oral anticoagulants (DOAC) are efficacy (at least as good as observed with warfarin), rare intracerebral bleeding events, and the absence of close monitoring requirements . HoweverEach stage of medication adherence  as proposed by the ABC (Ascertaining Barriers to Compliance) project around An intuitive solution would be an intervention that improves poor adherence in eligible patients . Such a By the identification of patients in need we technically mean prediction of future DOAC adherence, covering implementation and persistence after initiation was successful according to the ABC taxonomy. The benefits of predicting anticoagulation quality have been impressively shown for vitamin-K antagonists . NeverthThe aims of this study are thus to give a perspective of (1) which predictors should be considered when developing such a model predicting future DOAC adherence, and (2) how well this model would technically have to perform in order to be applied in a cost-efficient manner. Both goals explicitly deal with the  impact of thresholds on model development (1) and model performance (2). To approach the first goal, factors commonly associated with DOAC non-adherence in regard to all processes defining adherence were identified in a systematic literature search. We then investigated the performance requirements for such a prediction model to be implemented in a cost-efficient manner. Claims data was considered as a promising future area of application of such a model.We conducted a literature search following the PRISMA statement  in the PThe predictors that were finally identified in the categories of univariate, multivariate, or qualitative results of study analyses were grouped according to five dimensions of adherence . To explM&S) techniques were applied to investigate the impact of (non-)adherence and corresponding threshold effects on clinical outcomes, in particular thromboembolic events under AF treatment with the exemplary DOAC rivaroxaban. Of note, we modeled random non-adherence and did not consider non-persistence for reasons of simplicity. An extended pharmacokinetic-pharmacodynamic (PKPD) model yielded event rates in adherence groups separated at different thresholds as well as the risk for such an event by comparing these groups. Concerning the prediction model setting (B), we examined how the risk estimate between groups below and above a certain threshold is affected by imperfect discrimination between these groups. This relates to imperfect sensitivity and specificity. Considering the implementation of such a model to assess cost savings attributed to an intervention (C), we projected its cost-effective application. Based on an adherence improvement of some poorly adhering patients identified by the prediction model, we calculated cost balances by offsetting the interventional costs and saved costs by potentially averted clinical events. A detailed simulation protocol  the clinical setting, (B) the prediction model setting, and (C) the implementation setting. To begin with the clinical setting (A), Modeling and Simulation  and drug burden (10 studies) as the two most frequent predictor variables that were statistically significantly associated with non-adherence, while co-morbidity  was most often identified in multivariate analyses . SimilarNon-adherence patterns and attributed clinical risks were successfully incorporated into PKPD models to yield reasonable clinical effects . By separating the population with various adherence rates at a certain threshold, we obtained groups with clearly distinguishable survival curves representing the event-free proportion . Lowest Based on these threshold-dependent adherence effects, we applied imperfect discrimination of the threshold-separated groups. This mimicked the performance of an intended prediction model. Imperfect assessment of the true group status at various levels of sensitivity and specificity markedly decreased the detectable effect size . DespiteAddressing the clinically relevant challenge of poor adherence to DOAC treatments, our study diligently explored contemporary evidence to propose a plan facilitating the development of a model predicting future DOAC adherence of a patient exemplified by rivaroxaban. For the first time, we are presenting a comprehensive plan including associated predictor variables as candidate predictors together with expected requirements and benefits when developing such a model in an AF population in the future. Considering the burden of disease and potential benefits, our results should help guiding future research when an adherence model is applied and followed by suitable interventions aiming to improve or maintain adherence to medications.We found a considerable number of potentially associated predictors related to all different dimensions of DOAC adherence and persistence. Taking a closer look at the most frequently reported predictors , one has to admit that they are already well known, both for specific populations, particular drug classes, and for adherence in general . Some prOur study has several limitations: our literature search was able to provide merely exploratory results due to the heterogeneous nature of the eligible publications. The studies ultimately included were heterogeneous, consisted of many different AF (sub-) populations characterized by different co-medications and different comorbidities. This non-uniform setting may have influenced the results. Further on, methodological approaches differed markedly ranging from data collection by questionnaires to automatic assessments from claims data. Inconsistencies were equally prominent concerning, for example, the measurement of adherence or the definition of diagnoses as predictor variables.M&S parameters, we chose clinically reasonable estimates and thresholds at a pragmatic sample size achievable for most health insurance companies: considering the incidence of AF in Germany , a healIn conclusion, adherence and its associated predictor variables are extensively explored in the literature, while their suitability as predictors of future DOAC adherence needs to be empirically confirmed by actually developing the outlined prediction model. Beside these candidate predictors, patient characteristics, behavior, or attitudes going beyond these ubiquitous and readily available predictor variables should be explored. In order to assure cost-efficient implementation, a higher adherence threshold appears advisable to allocate interventional resources to patients at risk of falling below the 90% threshold. Clinical utility should focus on specificity to ensure the highest achievable benefit from such an intervention.Data extraction forms from the literature search and simulated data sets are available upon request from the corresponding author.ADM, CR, and LK were involved in preparation of the review protocol and development of the search strategy. CR and LK were involved in assessing abstracts and all full-text copies. All authors were responsible for data synthesis (where ADM acted as the third person for consultancy in cases of disagreement between two reviewers). ADM conducted the analysis related to the demands for model performance. ADM, CR, and WEH drafted and revised the manuscript. All authors read and approved the final manuscript.WH received consulting honoraria, speaker fees, or travel support outside the submitted work from the following companies: Bristol-Myers Squibb, Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Naturally occurring small molecule compounds have long been in the spotlight of pancreatic cancer research as potential therapeutics to prevent cancer progression and sensitize chemoresistant tumors. The hope is that terminal pancreatic cancer patients receiving aggressive chemotherapy can benefit from an increase in treatment efficacy without adding further toxicity by way of utilizing natural compounds. While preclinical studies on a number of natural compounds, such as resveratrol, curcumin, rapalogs and cannabinoids, show promising preclinical results, little has translated into clinical practice, though a number of other compounds hold clinical potential. Nevertheless, recent advances in compound formulation may increase the clinical utility of these compounds. Despite being the 12th most common cause of cancer diagnosis in the United States, pancreatic cancer is the 2nd most common cause of cancer death with a 5-year survival of 8.2% , with thPancreatic cancers are characterized by a number of complex genomic alterations that differentiate pancreatic adenocarcinomas from other malignancies. Pancreatic cancer develops through a specific series of mutational events (KRAS > CDKN2A > TP53/SMAD4) that develop gradually and independently . Recent Because pancreatic cancer is typically a disease of older patients, treatments are limited by the patient’s overall health and continuous aggressive treatments are often not an option in this patient population. Declining health in combination with the aggressive nature of pancreatic tumors and high levels of drug resistance limit clinical options for successful pancreatic cancer treatment and result in rapid disease progression with high mortality shortly after presentation .Natural products and synthetic small molecule compounds derived from natural chemical structures have long been in the focus of the pancreatic cancer field due to reports suggesting anti-cancer efficacy in a number of different malignancies and a low toxicity profile , 11. AddTaxanes are microtubule-stabilizing drugs that disrupt the cell cycle and are effective treatments against a range of cancers, including breast, ovarian, prostate, urothelial, and lung cancer –25. The Taxanes have high activity in a wide spectrum of solid tumors  and are active as single agents or in combination chemotherapy. However, their clinical use is accompanied by significant side effects .In order to increase the tolerability of taxanes and reduce resistance, efforts have concentrated on new taxane formulations , new taxane analogues and prodrugs. Compounds such as abraxane and docosahexenoic acid (DHA)-paclitaxel, are examples of new taxanes that have shown higher activity than paclitaxel. Both compounds display significant activity in taxane-resistant and unresponsive cancers while also exhibiting a safer toxicological profile than first-generation products.et al. using the combination in a large cohort of pancreatic cancer patients (n = 861). Patients in that study receiving the combination of gemcitabine and nab-Paclitaxel displayed increased survival (8.7 months) when compared to gemcitabine alone (6.6 months)  and andin viIn vitro studies have shown that EGCG inhibits cell cycle progression and induces apoptosis in pancreatic cancer cells, specifically in combination the chemotherapeutic bleomycin -epigallocatechin-3-gallate (EGCG) is the most potent catechin found in green tea. n Figure  75]. Ad. AdIn viLeiodermatolide is a polyketide macrolide found in the deep-sea sponge. It is known for its antimitotic properties and is thought to utilize a novel mechanism when compared to compounds with similar results, though the particulars of this mechanism have not yet been identified. Currently used compounds such as vinca alkaloids and taxanes induce cell cycle arrest by affecting the microtubules required for spindle formation and chromosome segregation. Preliminary data suggest that Leiodermatolide is potentially a potent inhibitor of pancreatic cancer .in vitro and in vivo, though it has not been studied as extensively as resveratrol. Studies have shown that that quercetin sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis, causes apoptosis in vivo and reduces tumor proliferation in vivo (Figure Quercetin, a flavonoid polyphenol closely related to resveratrol that is found in many fruits, vegetables and grains, has also shown promising results o Figure  20, 77], 77in viNatural compounds play a major role as anti-proliferative agents in pancreatic cancer therapy. While taxanes have successfully transitioned into clinical use and are now part of clinical routine in pancreatic cancer treatment, this class of compounds remains one of the few examples to achieve this transition. Despite promising preclinical results using a number of natural compounds, little has translated into the clinical routine of pancreatic cancer treatment although a large number of clinical trials have been performed on various compounds. This can be attributed to unspecified mechanisms of action, low bioavailability and difficulty ensuring patients’ compliance with the dosing regimen. This is further emphasized on the examples of curcumin and theracumin Table , where cFor natural compounds to become clinically relevant to pancreatic cancer treatment, these pitfalls need to be addressed. Taxanes are the only natural compound currently approved for clinical use in pancreatic cancer, though resveratrol and curcumin may be suggested as supplemental supportive care or taken by patents on their own accord.With continuous advances in medicinal chemistry and drug formulation, will enable the improvement of natural compound-based anti-cancer drugs and facilitate a transition of these compounds into the clinic.The wide variety of mechanisms of action associated with natural compounds is problematic in terms of isolating and confirming specific cellular targets and their impact on tumor cell survival. Though recent studies identified some mechanisms of action, we are far from understanding the full spectrum of effects that natural therapeutics have on normal and cancer cells. With recent drug development efforts aiming to increase the bioavailability of natural compounds, such as resveratrol and curcumin, the clinical use of these compounds become feasible by allowing the development of rational combinations with established chemotherapeutic agents.The combination of natural products and standard of care chemotherapy has the potential to increase quality of life and lifespan in pancreatic cancer patients, even though a number of hurdles need to be overcome for routine clinical use.


Anxiety disorders are the most common cause of mental ill health in the developed world, but our understanding of symptoms and treatments is not presently grounded in knowledge of the underlying neurobiological mechanisms. In this review, we discuss accumulating work that points to a role for prefrontal–subcortical brain circuitry in driving a core psychological symptom of anxiety disorders – negative affective bias. Specifically, we point to converging work across humans and animal models, suggesting a reciprocal relationship between dorsal and ventral prefrontal–amygdala circuits in promoting and inhibiting negative bias, respectively. We discuss how the developmental trajectory of these circuits may lead to the onset of anxiety during adolescence and, moreover, how effective pharmacological and psychological treatments may serve to shift the balance of activity within this circuitry to ameliorate negative bias symptoms. Together, these findings may bring us closer to a mechanistic, neurobiological understanding of anxiety disorders and their treatment. Anxiety disorders are the most common cause of mental illness in the developed world, with large social, economic and psychological impacts . A propeNegative Valence Systems, includes responses to aversive situations such as fear, anxiety, sustained threat and loss (/reward omission) that overlap with a key concept from the clinical psychology literature – negative affective bias. Negative biases in cognition are thought to promote and uphold key symptoms of many psychiatric conditions but are especially prominent in anxiety disorders, perpetuated by anticipation of – and uncertainty about – future events  information that promotes and upholds the anxious state while having knock-on effects in a wide range of other cognitive functions . In this framework, Beck proposed a cognitive triad illustrating a cycle among a negative view of the world, the self and the future. This model encompasses wide-ranging cognitive functions from memory to attention but nonetheless forms the basis of successful psychological treatments such as cognitive-behavioural therapy (CBT), highlighting potential advantages in taking a broad approach to linking cognitive research with clinical practice.To demonstrate our aim of bridging disparate experimental literature and clinical utility, consider We therefore review converging evidence across humans and animal models suggesting that negative bias may arise, at least in part, from activity within prefrontal regions and their interactions with subcortical regions . These cNegative Valence Systems domain of RDoC in animal models often makes a distinction between fear and anxiety. In the psychological literature, anxiety is defined as a prolonged state of heightened anticipatory arousal, often prompted by distal or unpredictable threats  and the prelimbic (PL) have been posited to play distinct roles in the expression and extinction of conditioned fear, with the IL supporting fear extinction as expressed by the amygdala and the PL conversely promoting fear expression as expressed by the amygdala  playing a key role in arbitrating this response. Indeed, across a range of paradigms in rodents, the PFC has been shown to play a regulatory role over BLA activation during fear expression, social interaction and anxiety-related behaviours .bi-directional effects of modulating BLA projections to the IL and PL during a number of behavioural assays assessing anxiety-like behaviour  circuit may serve to facilitate negative bias, while another  circuit may serve to suppress negative bias . This siPerhaps unusually for a symptom related to psychiatric disorder, negative bias in anxiety can be adaptive. For example, when one is walking home late at night and hears an unexpected noise down a dark alley, an appraisal of this situation as potentially threatening raises awareness, preparing the body’s fight or flight response in the event of immediate danger. In other words, negative bias in anxiety can promote harm avoidance. However, if this heightened anxiety and negative bias does not subside when one is subsequently safe at home, this response becomes maladaptive and can impair daily functioning . Thus, it was suggested by the pioneers of CBT that a biased appraisal of threat (i.e. negative bias) leading to catastrophising or excessive worry is a central characteristic of anxiety disorders . Dorsal Consistent with the animal work highlighted above, pathological negative bias in humans may in fact result in part from an inability to extinguish conditioned fear responses driven in turn by this altered, worry-related PFC responding . Healthydorsal PFC regions is broadly associated with increased negative bias. The dACC has also been linked to the adaptive control of behaviour as well as the risk of development of anxiety disorders  from early life are important contributing factors to the subsequent development of anxiety disorders . Cross-sreduced freezing behaviour, as would be predicted by the above reviewed evidence, but that it only did so in adolescent and adult rats, suggesting that the role of different medial prefrontal regions in negative bias changes across development. In other words, differences in fear responding, mediated by amygdala–medial prefrontal pathways, may partially be a result of a more protracted course of development and reorganisation in these cortical–subcortical pathways ) has long been implicated in the neuropsychopharmacology of anxiety , 2011, lincrease positive coupling within the same circuit shown to be elevated by induced anxiety , which is the largest long-term longitudinal study of brain development in the United States, currently in the process of collecting biological and behavioural data on over 10,000 children aged 9–10. Similarly, to gain an understanding of the underlying genetic contributions of anxiety, it is important to investigate the extent to which certain features and symptoms are heritable. This can be achieved through longitudinal twin studies , but maIn conclusion, work has begun to delineate overlapping neural networks involving the PFC and subcortical regions including the amygdala that may drive aversive responding and negative bias in both animals and humans. There is also promising evidence that pharmacological and psychological interventions can shape this circuitry and hence ameliorate negative affective bias. Future research should expand these findings to larger populations and investigate how these neural underpinnings arise in childhood/adolescence and change over time to shape behaviour.


Bronchiectasis is the final result of different processes and most of the guidelines advocate for a careful evaluation of those etiologies which might be treated or might change patients’ management, including cystic fibrosis (CF).CFTR mutations have been reported with higher frequency in bronchiectasis population. Although ruling out CF is considered as a main step for etiological screening in bronchiectasis, CF testing lacks of a standardized approach both from a research and clinical point of view. In this review a list of most widely used tests in CF is provided.Exclusion of CF is imperative for patients with bronchiectasis and CFTR testing should be implemented in usual screening for investigating bronchiectasis etiology. Physicians taking care of bronchiectasis patients should be aware of CFTR testing and its limitations in the adult population. Further studies on CFTR expression in human lung and translational research might elucidate the possible role of CFTR in the pathogenesis of bronchiectasis. Althoug females –5. These females –8.The pathophysiology of bronchiectasis might start with either structural airway damage or impaired mucociliary clearance, leading to subsequent chronic bacterial infection and a neutrophilic inflammation, which perpetuates this vicious cycle . BronchiBesides clinical phenotypes, one of the imperative steps in the management of patients with bronchiectasis still remains the evaluation of the underlying etiologies . Most ofAlthough the scenario concerning the investigation of bronchiectasis etiology is still evolving, both clinical and scientific communities agree on the need to rule out cystic fibrosis (CF). CF is an autosomic recessive disease caused by at least two mutations of a gene encoding a transmembrane chloride channel called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) involved in regulation of liquid volume and anions on epithelial surfaces.Ruling out CF in bronchiectasis patients is important in view of clinical, social-economical and psychological consequences. From a clinical perspective, CF is a systemic disease with extra-respiratory manifestations, which benefits from a specific management with a favorable impact on patients’ prognosis and quality of life . CF patiminimum bundle of investigations recommended by international guidelines on the management of bronchiectasis patients and the exclusion of CF is suggested only in the presence of specific clinical features [Staphylococcus aureus, Pseudomonas aeruginosa or Burkholderia cepacia in respiratory cultures, upper airway disease like polyps or chronic sinusitis, extra-respiratory involvement such as recurrent pancreatitis and maldigestion, or male infertility, see Table Although the majority of patients with CF are identified by newborn screening or during childhood, late diagnosis of adults is not infrequent . Howeverfeatures . These iCFTR genetic analysis as diagnostic standards, no hierarchical strategy of testing is suggested. An international consensus on the possible strategy to exclude CF in adults with bronchiectasis is still missing.In addition, there is no agreement across bronchiectasis guidelines on which diagnostic test should be used to exclude CF. While the majority of guidelines refers to sweat chloride measurement and The lack of common ground in testing bronchiectasis patients for CF has plenty of clinical and research implications. From a clinical perspective, CF testing seems to be inadequate among bronchiectasis patients. The national British Thoracic Society bronchiectasis audit reported testing for CF in 12% of the population , while tFrom a research perspective, several randomized controlled trials (RCTs) in bronchiectasis failed to meet their primary end-points and one of the reason might be because they did not account for the disease heterogeneity . This isNowadays, most CF cases are easily detected by newborn screening and diagnoses occur in clinically asymptomatic infants . On the The most widely used test in clinical practice to diagnose CF/CFTR-RD are listed in Table Measurement of chloride after sweat induction via pilocarpine iontophoresis is the first-line test to diagnose CF . A chlorhttp://www.genet.sickkids.on.ca/cftr/app) and standard mutation panels contain the most common CF-causing mutations (variable coverage depending on panel composition and ethnic origin of the tested people). Further steps like extensive sequencing of CFTR gene and search for large deletions or insertions may be indicated when two CF-causing mutations are not identified by a first level analysis but high clinical suspicion still remains. The classification of CF-causing mutations is still ongoing [www.cftr2.org).More than 2000 different mutations in CFTR gene have been reported  and intestinal current measurement (ICM) are used when sweat tests and mutation analysis are inconclusive and the clinical suspicion persists , 35. NPDRatiometric sweat secretion optical test is intended to assess CFTR function in vivo by comparison of CFTR-dependent and CFTR-independent sweat secretion . PresentPhysicians taking care of bronchiectasis patients should be aware that all the above tests might have some limitations in the adult population , 43. SweDiagnostic accuracy of genetic analysis depends on the testing strategy. CFTR gene panels can be designed to be high in specificity, as they test only for CF-causing mutations, at the cost of a relatively lower sensitivity. Sequencing and testing for deletion/duplication increase sensitivity, but reduce specificity by identifying CFTR variants of unknown clinical meaning.https://www.ecfs.eu/ecfs_dnwg).NPD is affected by a very high intra-test variability and several protocol variations and scores for interpretation are reported among different centers , 47. FurThe new assays as ratiometric sweat secretion optical test have not been validated yet in clinical practice and they are currently used in translational research. Figure Over the last decades, different investigators evaluated the role of CFTR in adults with bronchiectasis. Increased frequency of a single CF-causing mutation in azospermic men was firstly reported by Dumur in 1990 . Since tAlso interesting for the discussion is the hypothesis that even a single mutation in CFTR gene may contribute to the development of lung disease. On this side, it has been speculated that bronchiectasis may derive from a complex multifactorial interaction between genetic risk factors and environment. Other genes, so far unidentified, are likely to interact with CFTR activity in the development of the disease; in particular, altered sodium homeostasis due to mutations in ENaC channel is still poorly understood but may play a contributive role , 56.Next step in translational research could be the implementation of a lung genetic panel in bronchiectasis. The strengths of this panel would be a careful selection of genes based on current literature and the inclusion of all those mutations known to be target of new genetic modifiers as well as genes involved in lung inflammation. This approach could lead to new treatments based on better molecular understanding and different therapeutic targets. An individualized approach is necessary to understand the occurrence and contribution of ion channel functional status in bronchiectasis with the aim to evaluate the overall functionality of CFTR and, possibly, other ion channels. As factors not covered by the sequencing of the coding region and the exon/intron junctions could also influence CFTR function, even a sophisticated mutation analysis alone might not identify functionally relevant alterations. Recent developments in the field of stem cell research permit the collection of renewable tissue expressing CFTR and a detailed study of its channel function in organoids derived from minimally invasive rectal biopsies . The useRuling out CF is a cornerstone in etiological screening for patients with bronchiectasis and should be implemented in usual work-up for investigating bronchiectasis etiology. CFTR mutations, often with unclear pathogenic effect, have been reported with higher frequency among patients with bronchiectasis. Possibly, a single mutation in CFTR combined with other genetic and environmental factors might be involved in the pathogenesis of bronchiectasis. Further studies on CFTR expression in human lung and traslational research might elucidate the role of CFTR in bronchiectasis.


The design of Antibody Drug Conjugates (ADCs) as efficient targeting agents for tumor cell is still in its infancy for clinical applications. This approach incorporates the antibody specificity and cell killing activity of chemically conjugated cytotoxic agents. Antibody in ADC structure acts as a targeting agent and a nanoscale carrier to deliver a therapeutic dose of cytotoxic cargo into desired tumor cells. Early ADCs encountered major obstacles including, low blood residency time, low penetration capacity to tumor microenvironment, low payload potency, immunogenicity, unusual off-target toxicity, drug resistance, and the lack of stable linkage in blood circulation. Although extensive studies have been conducted to overcome these issues, the ADCs based therapies are still far from having high-efficient clinical outcomes. This review outlines the key characteristics of ADCs including tumor marker, antibody, cytotoxic payload, and linkage strategy with a focus on technical improvement and some future trends in the pipeline. Similar to conventional cancer treatments such as chemotherapy and radiotherapy, antibody immunotherapy and targeted therapies based on nanoparticulate structures are not safe and efficacious as often claimed; therefore, alternative therapies are urgently needed. In this regard, Antibody Drug Conjugates (ADC) technology that could bring forth a new generation of cancer therapeutics was the main focus of this study. ADCs are monoclonal antibodies (mAbs) connected by a specified linkage to antitumor cytotoxic molecules. The main components of an ADC and mechanism of its action are further demonstrated in In ADC technology, the specificity of an antibody for its immunogenicity is exploited to home a chemically supertoxic agent into tumor cells, while administration of unconjugated drug alone is not suitable due to its high toxicity. Therefore, ADCs can be further defined as prodrugs requiring the release of their toxic agent for their activation that commonly happens after ADC internalization into the target cell The first experimental design on ADC subject dates back to more than 50 years ago Clinical efficacy of the ADCs arises following accurate selection of four parameters including tumor targeting, antibody, cytotoxic payload, and method of antibody linkage to the payload. The precise selection of each parameter can be achieved through the knowledge gained from the previous studies and established ADCs, and is discussed here.e.g. CD30 and CD70 tumor necrosis factor signaling) can be considered as an advantage for ADC efficacy. Accordingly, the currently employed targets and their biological roles are listed in The important aspects of tumor markers in ADCs are demonstrated in For instance, glembatumumab vedotin is an ADC against an extracellular domain of non-metastatic B melanoma-associated glycoprotein (GPNMB) that is aberrantly expressed in various carcinoma including hepatocellular From the structure standpoint, a relevant antigenic determinant on cell surface membranes, termed Extracellular Domain (ECD), is required as an immunizing agent for antibody generation A further concern in the selection of the target for ADC is related to the homogeneity or heterogeneity expression of the tumor marker on the tumor cell surface. Homogenous expression of the tumor targets has been demonstrated to be more in favor of ADC targeting than those expressed heterogeneously The promising future of the ADCs supports extensive studies to look for a potent ADC target with a wide range of expression, from earliest cell recognizable lineage to maturation. This represents an exquisitely selective target that covers all types of malignancies. CD19 is a good example of such target that is highly expressed in B-cell and the vast majority of Non-Hodgkin lymphomas (NHLs), and B-cell Acute Lymphoid Leukemia (B-ALL) (99%) nM (Kd<10 nM) is commonly needed for the Ab component and accordingly for an effective ADC, based on frequency distribution histogram. The affinity of the antibody to its immunogen can affect the property of antibody which is termed as receptor-mediated antibody internalization. Receptor-mediated antibody internalization is a key mechanism underlying antibody endocytosis that is induced through antibody binding to its specific antigen Antibody component in ADCs undertakes both roles including being a carrier and targeting agent. The main aspects of the antibody in ADCs are demonstrated in nM Kd<0 nM is cIn addition to rapid internalization as a prerequisite for an antibody, the route by which antibody is internalized should be also considered, because it can potentially influence ADC processing Optimal pharmacokinetic (PK) properties including longer half-life is another aspect of the antibody component in ADC design via immune-mediated effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC), Antibody-Dependent Cellular Phagocytosis (ADCP), Complement Dependent Cytotoxicity (CDC), and cytokine signaling modulation in terms of inhibition or induction  in vitro than typical chemotherapeutic agents and are chosen based on their different actions on cancer and noncancerous cells. DNA modulators have significant effects on malignant cells as they are divided more rapidly than normal cells Taking a look at current cytotoxic drugs  shows thin vitro condition to determine whether it is a substrate, inhibitor or inducer of metabolizing enzymes , and some transporter enzymes like P-glycoprotein) in vivo factors that may be contributed to the elimination/enhancement of the cytotoxic agent Furthermore, a cytotoxic agent of the ADC is better to be studied in an in vivoRovalpituzumab tesirine is one example of ADC with PBD as a payload , that haThe cytotoxic payload should be also stable during preparation or storage and circulation in the blood. Cytotoxic payloads that are not fully stable can potentially be converted to undesirable drug forms during conjugation or storage. Solubility of the cytotoxic agent in aqueous solution is another important criterion in ADC design. Antibody is considered a protein and its conjugation to the cytotoxic agent must be performed in aqueous solutions with minimal organic cosolvents Cytotoxic payload should present a dominant functional group suitable for linkage to the antibody component of ADC The copy number and heterogeneity of antigen expression are the other important issues that must be considered in the selection of cytotoxic agent The ability to choose specified cytotoxic payloads with mechanism of action compatible with standard of care has been reported to facilitate clinical success of the ADCs in biopharmaceutical market. For instance, microtubule disrupting payloads are commonly chemotherapeutic drugs that are used for the treatment of cancers, including breast, ovarian and prostate cancer One of the dynamic research fields in ADC design is the study of the methods that are correlated with antibody conjugation to cytotoxic payloads, as it has a great role on balancing between ADC therapeutic efficacy and toxicity vs. >30%)  . HydroxyTheoretically, the linkage of cytotoxic payloads to the surface-exposed lysine of mAb occurs after reduction of ∼40 lysine residues on both heavy and light chain of mAb Due to low stability and safety properties of the pharmaceutical products with heterogeneous contents, they are complex to be accurately predicted in terms of efficacy or therapeutic window A conjugation through engineered cysteine residues that neither damages antibody fab region nor interferes with Fc-mediated effector functions, called THIOMAB technology e.g. selenocysteine Re-engineering of mAb is able to incorporate with unnatural amino acids, Incorporating a thiolated sugar analogue, 6-thiofucose, to the antibody carbohydrate that introduces new chemically active thiol groups using fucosyltransferase VIII Providing a ketone reactive group on antibody glycosylation site by glycotransferases Introducing an aldehyde reactive group on the antibody using sialyltransferase Genetically introducing specific glutamine tags to antibody whereby payloads with a primary amine group can be linked to the γ-carbonyl amide group of glutamine tags. Such reaction is catalyzed by a microbial transglutaminase which is capable of recognizing glutamines tags from naturally glutamines residues Staphylococcus aureus Sortase A enzyme Providing LPXTG tagged antibodies (A penta-peptide as a substrate for transpeptidation reaction) as specific linkage sites for the oligo-glycine-containing payloads, which are mediated by Conjugation of phosphopantetheine-linked payloads to the serine residues of the peptide-tagged antibodies via phosphopantetheinyl transferases catalysis Site-specific enzyme-mediated conjugation to genetically engineered antibody is as follows:e.g., providing two azide groups at asparagine 297 (Asn-297) residue in antibody constant region (Fc) is linked with cytotoxic payloads using copper-mediated click reaction Chemoenzymatic site direct conjugation, In this case, it is possible to reduce just two of four interchain mAb’s disulfide bonds of cysteine residues through carefully mild reduction conditions, as interchain disulfide bridges are more prone to reduction than intrachain disulfide bridges ADC as a potential targeted delivery system must be passed through all hurdles, including blood circulation, antigen binding, internalization, payload release, and eventual payload action. An unstable linkage can lead to premature release of the payload, before reaching the site of action Although a direct linkage between cytotoxic and antibody components has generally shown more stability in circulation e.g., protease or reductive agents) in the bloodstream compared to the cytoplasm Limited drug-linker designs for more than 70 current ADC clinical trials  are a die.g. MCC and MC linkers that link Ab to the payload via thioether linkage The current linkers used in ADCs are also broadly classified as cleavable and noncleavable linkers based on where they are cleaved into the cytoplasm. Cleavable linkers are those containing a conditional cleavage sites sensitive to be cleaved immediately after ADC internalization, such as VC, SPDB, SPP, and hydrazine which can be triggered through protease reactions, glutathione reduction, and acidic pH, respectively Characteristics of ADC target such as copy number, internalization rate and level of homogeneity should be considered in conjugation method and linker selection. For instance, ADC with disulfide-linkage has been shown to have more cytotoxic activity than the same ADC with thioether linkage when they were directed to the tumor cell lines expressing a low copy number of targeted antigen Cleavable linkers may increase the possibility of bystander effect In vivo adverse effects of ADCs are influenced by the use of cleavable or noncleavable linkers. As in the case of tubulin inhibitor payloads, which is linked through cleavable linkers to the antibody component, e.g. SPDB-DM4 (Ravtansine-DM4), or VC-MMAE, peripheral neuropathy can be frequently observed, whereas noncleavable linkers often trigger hematological toxicity, possibly due to an increased dose and interactions with Fcγ receptors on hematopoietic cells The type of linker plays an important role in ADC catabolite products with regard to processing into targeted cells or metabolizing by clearance mechanisms. The type of ADC catabolites may influence some ADC features such as IC50, Maximum Tolerated Dose (MTD) ADC is considered exciting and promising antibody-based therapeutics to improve cancer therapy. Growth in the number of registered ADCs in clinical trials  represeni.e. tumor marker, antibody, cytotoxic payload, and linkage strategy would be required to prepare a successful ADC.The design of an ADC might seem to be not very complex, while several issues must be taken into consideration to complete ADC’s potential as a therapeutic agent for cancer. This might be the main reason for the condition that small number of ADCs have reached the market . The majvs. normal cells, presenting cell surface immunogen, and being capable of performing ADC internalization.With regard to ADC tumor markers, they do not have to be involved in tumor growth via antibody improvement. Antibody engineering technology for production of alternative bsAbs to design more efficient ADCs (bsADCs) has been proven in several preclinical models High specificity, adequate affinity, and receptor-mediated internalization are the major aspects of antibody choice. Efforts to optimize antibody component would be a great idea to translate into improved ADCs. In fact, some major ADCs’ weaknesses including, low efficiency Another main concern in the development of ADCs is related to the study of finding cytotoxic payloads that are potent enough with confined DAR (Up to 7 drugs per antibody) e.g. thiol, amine groups) is the other interesting subject, as it eases the conjugation process. One further challenge of ADCs is associated with the limitation of linkage and conjugation chemistry to link an optimized number of the payloads to the antibody in predefined location homogeneously.In contrast, the introduction of innovative methods to modify ADCs cytotoxic payloads with versatile functional groups (Interdisciplinary and multidisciplinary works and related studies such as recombinant DNA technology, bioconjugation, and chemistry are the hopeful strategies to get the purpose of achievement in site-specific conjugation and homogeneous ADCs Based on promising reports from research to synthesize homogeneous ADCs, it is likely that the first ADC products constructed using site-specific conjugation will be made for cancer therapy that may hold the promise about the future use of ADCs.Taken together, despite challenges in ADC design, the future of ADCs seems to be much promising as more clinical trials and basic researches conducted on existing ADCs would pave the way to tackle issues regarding tumor marker, antibody, cytotoxic payload, and linkage strategy.


The present work is a reanalysis of prior work documenting postural sway in phasmids  . The pri Postural sway is pervasive feature of context-sensitive, goal-directed behaviors. It spans such a wide range of species that, at first glance, it seems that the research questions surrounding postural sway in one species have little to do with another. For instance, in a human model, postural sway raises questions about stability of upright standing and fall risk, one of the leading causes of death in the elderly . In theiIn the present work, I revisited evidence from postural sway in phasmid and attempts find a geometric parallel between phasmid postural sway and human postural sway. Far from attempting to make an abstract geometrical comparison interesting in its own right, I propose that this geometrical resemblance may point to deeper connections in terms of commonalities in how these different species make use of perceptual information. Much like the rest of human movement physiology from autonomic to voluntary processes –14, the The tensegrity hypothesis originates from neither insect nor human behavior but comes from work originating in cell and tissue biology suggesting that various biochemical and physiological processes depend on a vast network balancing tension and compression elements built across many spatial scales. The term “tensegrity” is a portmanteau short for “tensional integrity.” This multiscale network encompasses actin-myosin chains at the cellular level, extends across the extracellular matrix (ECM), and continues up (in vertebrates) to the macroscopic scale of musculoskeletal system where muscles serve as tensional elements balanced with the compression elements provided by bone. At this musculoskeletal scale, the connective tissue analogue to extracellular matrix appears as the fascia, an extremely tensile material whose manifold deformations provide global, contextual support for the more focal events of action potentials and flexions of innervated muscle tissue. Tensegrity architecture supports “mechanotransduction,” the rapid propagation of local perturbations across the global architecture of an entire cell, tissue, or organ—at speeds beyond the limits of more local modes of transmission, such as second-messenger systems or neural transmission .It is these “ultrafast” propagations of perturbation across vast distances within biological systems ;23 have Some of the difference in receptivity in different fields has much to do with the fields’ difference reliance (or not) on the freedom to build an autonomous system and, likewise, the fields’ different reliance (or not) on randomized controlled trials to adjudicate the identification of a cause. To some degree, it is no surprise that the appreciation for tensegrity structures in robotics has outpaced the appreciation for tensegrity structures in behavioral and psychological sciences. The roboticists have the luxury of being able to build their own systems. The challenge for behavioral and psychological scientists is that our model-organisms’ bodies come as they are, and for centuries, we have been paying more attention to the more focal events in relatively localized, relatively stable components of our model-organisms’ anatomies. Better appreciating this tensegrity-like background, global support requires no small change in perspective, and what’s more, if the promise from both robotics and from cellular and tissue-focused biology is true, then it confounds behavioral-scientists’ best hopes to respect long-held wisdom in experimental design.To put a finer point on it, the primacy of the randomized controlled trial (RCT) is an age-old value governing how behavioral and psychological sciences assign causal status. If the tensegrity structure is so intimately involved in so many of the better-known, more focal dynamics amongst anatomical parts, then there may be no ethical or practical control condition wherein we might remove the tensegrity structures to see what happens. Certainly, we know from recent research in regenerative medicine that one of the best supports for scaffolding the re-growth of atrophied muscle tissue is the experimental insertion of a “quilt” of extracellular matrix , and thiAn empirical-geometrical approach offers a falsifiable foothold from which behavioral and psychological scientists may develop more elaborate models of the causes. That is to say, it may be beneficial for scientists interested in the tensegrity hypothesis to focus their efforts around the proposal that tensegrity-driven systems are necessarily multifractal systems . This prUltimately, this paper is about elaborating tensegrity-themed perspectives and about phrasing the primacy of multifractal geometry over ultrafast responses as a privileged way forward in articulating the content of any tensegrity-based theory. The steady inventory of ultrafast responses will continue and has likely not come anywhere near to its conclusion. The crucial rhetorical value of ultrafast responses in theoretical discourse about context-sensitive, goal-directed movement coordination goes something like the following:Commitments to inferential models based in neural tissue can only predict behaviors unfolding over the time that electrochemical transmission needs to unfold itself.Many ultrafast responses are too fast for electrochemical transmission to precede.So, what responds with ultrafast latency requires something other than electrochemical transmission.A major payoff of accruing a large inventory of ultrafast responses is that we can add new straws to the computational-neuroscience camel’s back in the hopes that—maybe, just maybe—each latest evidence of ultrafast response will turn the scholarly tides away from computational neuroscience towards more ecological perspectives cognizant of tensegrity principles. However, a major risk of building this large inventory of ultrafast responses is that each of these ultrafast responses indicate alluringly to the “something else” other than electrochemical transmission, but this ultrafast-response rhetoric remains empty, and frankly, it seems unrealistic that effects skating upon connective tissue faster than neurons can support should alone inspire an about-face away from computational neuroscience. For instance, the fascinating work of Stepp, Moreno, and Turvey  showed uIn light of what we know now, simply pursuing ultrafast responses to the exclusion of using multifractal geometry is wrong-headed on many counts. We now know that the “something else” supporting ultrafast responses belongs to a class of distributed architectures called “tensegrity” because the ultrafast response involves a whole-organism integrity written into a hierarchical balance of tensions. We seem to becoming towards consensus that tensegrity architectures are best understood with multifractal geometries capable of articulating cascade-like interactions across time scales. Seeking for examples of what neurons cannot do alone seems to beget unconstructive dichotomies between tensegrity and nervous system—which dichotomies are unconstructive because the tensegrity structure of movement systems is possibly exactly what underwrites the nervous systems embedded in those movement systems. So, ultrafast responses are informative, but they bypass the more pressing question that many more scholars might want answered: namely, how the nervous system participates in the movement in non-computational but fully ecological ways.The present work is a call to arms for ecological perspectives on movement coordination to use multifractal geometry as the lens on dexterity that Turvey and Fonseca  promisedThis more specific hypothesis does demand answer to the question “What is multifractal geometry?” Certainly, on first acquaintance, the proposed greater specificity and falsifiability comes at the cost of seeming like more jargon. However, multifractality may be understood as generalization of concepts from linear statistics to encompass measured systems that do not distribute as homogeneously and independently as linear statistics assume.SD). Fundamentally, the assumption of independence makes homogeneity of variability around the mean inevitable but leads specifically to the expectation that SD should increase with the square root of time, that is, as a single power-law of time, i.e., SD ~ t.5. Measured systems become less homogeneous and more patchy as those measured systems embody progressively less independence across sequential events.Linear statistics presume that systems distribute homogeneously and that each new event is independent from the previous event. Events appearing independently from the previous leads to an aggregate that has a) central tendency best approximated by the arithmetic mean and b) width beyond the central tendency best approximates by the standard deviation . Multifractality entails that measured systems have a continuum of fractional exponents, often called a spectrum, and this range is effectively the width W of the multifractal spectrum.Empirical estimates of multifractal geometry appear only after we introduce gradually more dependence across sequential events. We can briefly provide the short-hand understanding that multifractality is, roughly speaking, a SD is most often useful for describing variability of homogeneous processes. So, although examining the multifractality through these SD-defining power-laws is certainly useful lnLjand wherLj)]lnLj.The scal methods .q available to test may seem alarming, but it follows in the tradition of theoretical recommendations from Mandelbrot )reduction in sway. Hence, no matter the sensible movement-outcome focus of Bian et al.’s [An important caveat here is that the appearance of “tensegrity” as a sway-reducing mechanism in the present reanalysis is by no means the general rule. And this caveat contains within it lessons about ecologically valid definitions of stability based on movement-based outcomes. Bian et al.  approachet al.’s  view of It was in this shortfall in the evolutionary survival account where I saw an opportunity to test the tensegrity hypothesis: multifractal structure might reveal an explanation for the reduction in sway. Explanatorily, an evolutionary imperative to survive through motion camouflage and so to avoid predators will lead wind stimulation to prompt more sway in the long term. However, the facts of postural sway are much more nonlinear than this evolutionary account predicts. Indeed, the finding that inspired Bian et al.’s work was Bässler and Pflüger’s  observatUltimately, human movement science needs ecologically valid definitions of stability because “stability” is not just “less sway.” However, an important challenge of current movement science is that, despite recognizing that “some sway” is better than “no sway,” despite recognizing that variability can be an important substrate for supporting movement coordination , there itMF statistics offer a way to classify the type of nonlinear interactions across scale that the tensegrity systems can use to support context-sensitive behavior.The importance of this work is that it offers a new lens through which to find similarities in movement coordination across radically disparate species. No matter the disparity in anatomical configuration, humans and phasmids appear both to sway with multifractal complexity, and both species’ postural sway has multifractal complexity significantly different from the best-fitting linear model of sway. Postural sway may follow from similar tensegrity-like principles across different species, and it may be that As for helping to elaborate the tensegrity hypothesis, the usefulness of multifractal modeling may bring further benefits. The foregoing work has proposed that multifractal modeling in conjunction with comparison of multifractal results with best-fitting linear models provides a falsifiable hypothesis. If multifractal modeling can provide a falsifiable window onto tensegrity principles supporting context-sensitive behavior, then it may provide a common language with which the empirical research on various model organisms can integrate a common understanding. An important promise of the tensegrity hypothesis lies in the possibility that tensegrity principles span multiple scales, and a corollary of that promise may be that the tensegrity hypothesis should apply invariantly across organisms whose morphology and behavior reside within nonoverlapping scales.The potential efficacy of multifractal modeling for quantifying the contributions of tensegrity principles to observed behaviors could also refine the tensegrity hypothesis beyond the bare demonstration of ultrafast responses. No doubt, ultrafast responses present an elegant contrast in which it becomes clear that organismic behavior is faster and more context-sensitive than neural dynamics are able to support. However, the future of tensegrity hypotheses for behavioral and psychological sciences may lie ahead in the challenge of articulating the coordinations of tensegrity structures in conjunction with neural dynamics and not simply before neural dynamics. That is to say, a tensegrity hypothesis that focuses only on the ultrafast response may be missing out on the rich possibilities of modeling how tensegrity could have an ongoing contribution to neural events long after the ultrafast response and even after the neural events have begun. The current state of the art is for the estimation of multifractal geometry to answer questions about the relevance of cascade-like tensegrity structures. Simply stopping short at ultrafast responses is to cheapen the full form of the modern tensegrity hypothesis, and multifractal modeling may now be the proper, privileged way to convert the tantalizing ideas behind tensegrity-themed theories into empirical answers to our questions about movement coordination.