In this article, we review recent advances in research on rhythm and musical beat perception, focusing on the role of predictive processes in auditory motor interactions. We suggest that experimental evidence of the motor system’s role in beat perception, including in passive listening, may be explained by the generation and maintenance of internal predictive models, concordant with the Active Inference framework of sensory processing. We highlight two complementary hypotheses for the neural underpinnings of rhythm perception: The Action Simulation for Auditory Prediction hypothesis  and the  The coupling of action and prediction in perception has been characterized by predictive models of perception  includinHowever, this classical PC/Bayesian account of perception characterizes the brain as a passive, Helmholtzian, stimulus-response machine, responsive only to the generation of prediction errors between its top-down sensory predictions and the actual sensory input from the world . Our braprecision, or uncertainty–of the original sensory prediction, in addition to counterfactual predictions related to how these prediction errors and their precision would change in response to active motor engagement with the sensory stimulus. Expected precision is modulated by sensory context and active engagement with the sensory signal. The generation of internal, predictive sensorimotor timing signals aligned to the musical beat may enhance the prediction and precision of temporal expectancies when perceiving syncopated musical rhythms, such as in musical groove  PC/Bayesian processing of music in general . Howeverormation , and is ormation . This diormation .Concordantly, the motor system has been found to be consistently active when listening to music, even in the absence of specific motor movement. A recent meta-analysis of fMRI studies found clusters of activations in key regions of the motor system in passive music listening, including bilateral premotor cortex and right primary motor cortex . MetricaStrong explanations of rhythm perception must account not only for prediction in action, but also for the role of the motor activity observed in passive music listening. Below, we provide an overview on the motor system’s role in rhythm perception, and review two complementary hypotheses which highlight the causal role of the motor system in beat-based timing perception.Rhythm perception involves two types of timing perception, interval-based (absolute) timing and beat-based (relative) timing . Intervamotor system in the perception of rhythm, and support growing consensus on the role of motor pathways in the formation of internal predictive models in perception more generally.Complementary to the ASAP hypothesis, the GAE hypothesis has been proposed to account for differences in beat-based temporal processing between primates and humans see  also posvocal learning abilities, which strengthened tight audio-motor connections in the dorsal auditory stream underlying rhythmic entrainment along the primate lineage.One important difference between the ASAP and GAE hypotheses is that ASAP purports to explain the presence of motor activity in beat perception even in the absence of overt movement, while GAE explains how evolution within motor pathways enables physical entrainment–synchronized movement–to a rhythmic stimulus. ASAP claims that beat-perception in humans arose with the emergence of In contrast, GAE favors a gradual strengthening of these connections over evolutionary time, building on specific interval-timing mechanisms already extant in the mCGBT circuit of the primate brain. The result being the formation of an additional beat-based mechanism with enhanced connection of the mCGBT to the auditory cortex via that same dorsal auditory stream in the human brain . Recent In addition to fMRI observation of motor activation in music listening and rhythm processing, the predictive and causal roles of specific motor structures highlighted by the ASAP and GAE hypotheses have been experimentally tested via electroencephalography (EEG) and transcranial magnetic stimulation (TMS). Specific Event Related Potentials (ERPs) relating to prediction errors evoked by rhythmic deviations in musical stimuli include the mismatch negativity (MMN) and P3a . These aAction Simulation for Auditory Prediction has been further supported by TMS research, demonstrating causal links between specific types of beat processing and regions of the dorsal auditory stream. A set of TMS experiments evaluated the role of the posterior parietal cortex (PPC), which is thought to serve as an interface for bidirectional communication between auditory and motor regions of the brain, and the dorsal pre-motor cortex (dPMC), which is also part of the dorsal auditory stream and is associated with movement planning and synchronization to auditory stimuli . By downWhile there is growing consensus that the motor system is causally involved in timing and rhythm perception, and that the neural substrate includes cortical structures of the dorsal auditory stream and subcortical structures within the motor-cortico basal ganglia thalamo-cortical loop, the specific neural mechanisms which enable timing and rhythm perception within these substrates remains an open question. For some years, cognitive scientists have been looking for how internal timing can be instantiated by patterns of temporal stimuli via, e.g., clock-based or oscillatory mechanisms . Given tContinuous state-space models have also been proposed in Active Inference accounts for the generation of predictive models in action and sensory processing more generally, neurally mediated by the balance of pre- and post-synaptic activity  and neurIn this paper, we reviewed recent advances in research on rhythm perception, focusing on the role of predictive processes in auditory motor interactions in beat-processing. We highlighted two complementary hypotheses for the neural underpinnings of rhythm perception: The ASAP hypothesis  and the internal predictive models of beat-based timing. If motor activity is causally involved in the formation of auditory predictions, then causal TMS manipulation to down-regulate activity in, e.g., parietal cortex or dPMC should result in the reduction of MMN and P3a event related responses to perceptual deviants in rhythmic stimuli, and this response might differ based on whether the stimuli contains timing deviants related to tempo or phase. Future research should include stimuli designed to elicit specific prediction errors with perceptual deviants, such as in oddball paradigms, while measuring event-related potentials associated with predictive processes in combined EEG and causal TMS experiments. Results from these experiments could extend and strengthen already emerging support for GAE and ASAP, as well as further contextualize the role of Active Inference in music and beat-based timing perception.Future work in understanding the neural, cognitive, and behavioral dynamics of musical beat perception in humans should investigate not only the sensorimotor processes responsible for the perception of rhythm, but also the specific neural mechanisms by which top-down predictions serve to modulate driving proprioceptive sensations arising from concrete actions of the body or abstract activity of the motor systems. While EEG experiments e.g.,  point toSP and RB conceptualized the manuscript. BM, DC, and AP contributed to the writing and the exhaustive analysis of the literature. All authors contributed to the article and approved the submitted version.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.


In the last few decades, solid dispersion (SD) technology had been studied as an approach to produce an amorphous carrier to enhance the solubility, dissolution rate, and bioavailability of poorly water-soluble drugs. The use of suitable carrier and methodology in the preparation of SDs play a significant role in the biological behavior of the SDs. SDs have been prepared using a variety of pharmaceutically acceptable polymers utilizing various novel technologies. In the recent years, much attention has been paid toward the use of novel carriers and methodologies in exploring novel types of SDs to enhance therapeutic efficacy and bioavailability. The use of novel carriers and methodologies would be very beneficial for formulation scientists to develop some SDs-based formulations for their commercial use and clinical applications. In the present review, current literature of novel methodologies for SD preparation to enhance the dissolution rate, solubility, therapeutic efficacy, and bioavailability of poorly water-soluble drugs has been summarized and analyzed. Further, the current status of SDs, patent status, and future prospects have also been discussed. Moreover, the phase separation can be mitigated by maintaining low molecular mobility of the matrix and drug during SD manufacturing process. The molecular mobility of the amorphous system depends on the composition and manufacturing process  were withdrawn from the market. It is evident for its withdrawal from the market due to recrystallization  of the drug from supersaturation solution on ageing. A thorough understanding of physicochemical features of drug, solvent, and matrix play a prime role to avoid possible chances of challenges. The sequential steps for formulation development of SDs are summarized in The paradigm of solubility challenges faced by formulation scientists is still largely unchanged. The poor aqueous solubility and subsequent dissolution rate of any drug are one of the most considerable challenges during formulation design and development. For the last two decades, the drug discovery and selection of new chemical entity (NCE) have taken a comprehensive scrutiny process through the use of combinatorial screening tools such as combination high throughput screening  and crystalline drug . The selection of carrier/matrix is a very important and critical step in the formulation of SDs. Based on the physical state of drug, the second generation SDs further classified into amorphous solid solution and amorphous solid suspensions , Tween 80, and Compritol were commonly used to prepare this type of SDs. Among these surfactants, Poloxamer is the most commonly used carrier and recently Soluplus has shown very significant result in the preparation of SDs by melt extrusion technology . The two main targets can be achieved by preparing CRSDs like enhancement of drug solubility and controlled drug release pattern. In this type of SD, the poorly water-soluble drugs molecularly dispersed in the carrier. It can deliver an optimum amount of drug for an extended period. There are wide range of advantages are reported for poorly water-soluble drugs  and ultra-rapid freezing (URF). These methods of SD preparation work on the principle of increasing the freezing rate compared to the conventional freeze-drying technique. In both of these methods, the procedure is performed under sub-ambient conditions. There may be fewer chances of drug degradation due to no contact between heat or air that may promote drug degradation during the drying process. In the SFD technique, the reduction of particle size takes place without the application of intense frictional or mechanical forces which lead to the degradation of drug particle by thermal stress  ratio showed significant enhancement in the drug solubility compared with pure drug. The enhancement was found to be of 630-fold in comparison with the pure drug  formulation showed elongated particles, complete lack of crystallinity leads to a significant increase in the dissolution rate and bioavailability  SDs to investigate the bioavailability on rat model using PEG 4000 and Kolliphor3.5.Microwave irradiation (MWI) is electromagnetic irradiation found between the infrared (IR) and radio frequencies in the range of 0.3–300 GHz. Most of the MW works at a frequency of 2.45 GHz . The microwave can easily penetrate in any materials and at the same time allows the generation of heat at any point of the sample. The characterization can be done by the presence of dipole moment in the molecules which help to absorb the MW energy and transform it into heat  SDs were prepared and evaluated for the enhancement of solubility and dissolution rate. The SDs were prepared using the solvent-free MWI technique using the different carriers. The prepared MWI samples were characterized for physicochemical parameters and drug release profile. The prepared SDs revealed enhanced dissolution rate of both drugs using PEG 400 carrier as compared to other carriers. The selected SDs showed significant % inhibition in comparison with pure MA (68.09% after 4 h) and pure FFA (55.27% after 4 h)  is used as a solubilizing solvent or anti-solvent. There are a number of favorable properties like the low surface tension, high diffusivity, and low viscosity and the pressure can be easily adjusted. It can easily control the solubility of many drugs  and AUC were increased up to 3.6-fold and 3.4-fold, respectively, in comparison to pure drug  and also found highly efficacious than pure MA  by formulating SD using HME technology. The prepared samples were further evaluated for drug release, solubility studies, and permeability characteristics. The findings of the study revealed a significant enhancement in piperine % release, and solubility enhancement was more than 160- and 45-fold in water. Furthermore, the permeability studies result revealed the enhancement in piperine absorption of 10%  and succinic acid (SA). The solid-state characterizations were performed using SEM and DSC and the results demonstrated the transformation of the crystalline state to an amorphous state in the SDs formulations. The prepared formulation enhanced the solubility, release of drug and also significantly enhanced the oral bioavailability (Cmax and AUC) compared to the pure drug  to evaluate the physicochemical property of the developed formulation. The prepared formulation showed formation of amorphous composites at different polymer content. There was a significant increase in dissolution was observed for both the used drugs. The ternary SD of carbamazepine: nicotinamide was prepared by extrusion method using the carrier HPMC, SOL, and PVPVA64  at different screw speeds and temperature. The dissolution study results revealed an immediate release pattern with about 80% drug release achieved in 45 min study with SDs containing the combination of MgO, PEG, and Kollidon as compared to the pure drug, binary mixture, and physical mixture  for the material and also avoids the thermal stress to the carrier and drug  in a rat model  in drug release that was observed in comparison to pure drug and physical mixture. The formulation also showed greater anti-inflammatory activity by achieving edema inhibition (up to 90%) in 6 h, whereas pure drug depicted lesser edema inhibition (77%) in the same time. In another research, ultrafine grinding technology and HME technique were employed to prepare Angelica gigas Nakai solid dispersion (AGN-SD) and evaluated for the antioxidant and anti-inflammatory activities  as compared to pure drug. In another study, valsartan loaded SD was prepared by using Soluplus® and d-alpha-tocopherol PEG 1000 succinate as a carrier  enhancement in bioavailability compared to pure coarse powder. Rashid et al.,  with a faster Tmax value achieved with the prepared SD in comparison to revaprazan powder. In another research, the same research group prepared ezetimibe SDs using HEC and Tween 80 to evaluate the oral bioavailability  drug controlled release and in second type the release followed (b) carrier controlled release. The prepared drug carrier matrix dissolves or absorbs water quickly due to their hydrophilic property. In some cases, there is a formation of concentrated carrier layer or gel layer. When the drug dissolves in this gel matrix and due to the high viscosity the diffusion of drug diffusion is difficult. It is a rate-limiting step and diffusion of the carrier into the bulk phase. The insoluble or sparingly soluble drug releases into the concentrated layer and release intact after coming in contact with the dissolution media. The release profile also depends upon the particle size, drug solubility, and drug polymorphic state Craig, . If the 7.Researchers are showing their interest in new methods to enhance the solubility and dissolution rate of poorly water-soluble drugs. Several patents are being filed every year related to the SDs. In this review, we tried to tabulate the published patents on SD, their patent number, publication title, inventor/assignee, and year of publication. The literature review was done from the year 2015 to 2019. Google patents were exploited to search published patent contents. For extensive search, the keywords namely SD was used and the search was filtered to compress the results to last 5 years only. 8.®, Kollicoat® IR or Inutec SP1, Inulin®, Gelucire®, and Pluronic® are used alone or in combination with the different polymers have broadened their application in the formulation of SDs  investigations have proved the feasibility of SD as a potential carrier for oral drug delivery applications. There are various novel technologies that have been used in the preparation SDs to enhance the biological profile. Nevertheless, clinical studies have been poorly reported on SD systems and hence more in vivo studies are also required to support the in vitro data.SDs strategies have been studied extensively for the enhancement of solubility, dissolution, and bioavailability of poorly water-soluble drugs. To enhance the dissolution and bioavailability of such drugs, the modification of their physicochemical properties is essential. Several natural, synthetic and semi-synthetic polymeric carriers, and surfactant have been studied to modify the physicochemical properties. The reported


Heart failure (HF) is a complex clinical syndrome in which the heart is unable to provide an adequate circulatory output to meet the physiological requirements of the body . It can MicroRNAs (miRNAs) are a collection of 19–25 nucleotide endogenous, non-coding RNA molecules that act as post-transcriptional gene expression regulators and may potentially serve as novel diagnostic biomarkers or therapeutic targets ,4. TheirWith a growing interest in this area, a recent study by Shah et al. (circulation) identifies a subset of miRNAs that predict left ventricular reverse remodelling (LVRR) in HF patients with reduced ejection fraction . LVRR peIn this study, 64 participants from the PROTECT trial  were identified and circulating miRNAs were prospectively measured from plasma samples. In total, 11 miRNAs were recognized to correlate with LVRR post-guideline-based medical therapy for approximately 10 months. Their target genes were subsequently identified using bioinformatics approaches. Furthermore, three of these miRNAs led to a significant downregulation of a set of targeted mRNAs, which were not previously determined in the pathogenesis of HF. The dysregulation of human miRNAs  alleviated the expression of targeted mRNAs via common pathways in both cellular and mouse models. The evaluation of these miRNA pathways showed an overlap of pathways consistent with myocardial hypertrophy and HF.This study supports the evolving evidence that miRNA networks are crucial in the pathogenesis of HF. Moreover, it illustrates multiple plasma miRNAs associated with LVRR in a carefully phenotyped human cohort. The investigators utilized a multiplex circulating miRNA assay (FirePlex™) for quantification of miRNAs in the study. In general, multiplexing technologies such as the FirePlex™ system used by the investigators need to be validated on single-plex assays over another platform. The RNA isolation methodology should involve the use of synthetic spike-in miRNAs and the normalization/adjustment for any loss of sample during the processing workflow. Methodologies involving robotics and automation need to be introduced in the isolation of miRNAs or total RNA from biofluids and the coefficient of variation between users should be stated to assure the reproducibility of findings in subsequent studies.As mentioned by the authors, study limitations include small sample size and inability to derive general conclusions given the absence of an external cohort. It also needs to be noted that most of the changes in levels of the miRNAs presented as relative to control are modest and that significant changes (>2-fold) in the levels of these miRNAs should be investigated using absolute quantitation approaches involving droplet digital PCR so as to understand the biological relevance of each miRNA. The FirePlex™ technology used by these investigators involves endpoint  assessment of miRNA amplification. As indicated by the authors, a Pearson (rather than spearman) correlation of 0.74 was observed between the FirePlex™ and qPCR platform. Another limitation of the study, as discussed in the supplemental section of this study, is that all samples were analysed on a single assay plate. Future studies need to involve rigorous assessment of study samples to test batch variation, intra- as well as inter-user variation and provide more clarity in data presentation to facilitate reproduction of study findings by others in the field. It should be noted that technologies involving real-time PCR and droplet digital PCR should be used to assess transcripts that are of low abundance and yet relevant to vascular complications and disease.Apart from these molecular/technological limitations, precision regarding the exact timing of echocardiographic follow-up could have potentially enhanced the association between miRNAs and LVRR. In addition, the animal investigation did not include genetic or pharmacological gain- and loss-of-function analysis of non-coding RNAs associated with LVRR. Theoretically, this may blur the exact role of these miRNAs in the pathogenesis of HF. CRISPR-based gene editing technologies could be used in future to assess the potential of these miRNAs as modulators/biomarkers of disease.Moving forward, further clinical trials encompassing stringent endpoints and appropriate study designs are required to assess the potential utility of miRNAs in clinical practice.These should focus on a thorough recognition of corroborating changes in the myocardium and plasma of model systems with coherent results in humans. Precise identification of the cellular origin for these miRNAs will highlight the dominant tissues involved in the pathogenesis of HF. Overall, this study serves as a molecular discovery platform which enables further research into the extended role of miRNAs as a clinical biomarker, prognostic tool and potential therapeutic target .


Non-alcoholic fatty liver disease (NAFLD) is a major health problem associated with obesity and other features of the metabolic syndrome including insulin resistance and dyslipidemia. The accumulation of lipids in hepatocytes causes liver damage and triggers inflammation, fibrosis, and cirrhosis. Beside fatty acids and triglycerides, evidence showed an increased accumulation of free cholesterol in the liver with subsequent toxic effects contributing to liver damage. The maintenance of cholesterol homeostasis in the body requires a balance between several pathways responsible for cholesterol synthesis, transport and conversion into bile acids. Intestinal absorption is also one of the major determinants of cholesterol homeostasis. The nature of changes in cholesterol homeostasis associated with NAFLD has been a subject of extensive investigations. In this article, we will attempt to provide a brief overview of the current knowledge about the disturbances in cholesterol metabolism associated with NAFLD and discuss how certain molecular targets of these pathways could be exploited for the treatment of this multifactorial disease. Histtoxicity . Howevertoxicity . Understde novo synthesis and intestinal absorption of cholesterol, whereas the output pathways include the excretion of free cholesterol in bile, the conversion into bile acids, and the non-biliary trans-epithelial cholesterol efflux (TICE) in the intestine  as well as the epithelial cells that are shed into the lumen (~300 mg/day) and biliary cholesterol . A total amount of ~1,400–1,700 mg of cholesterol is presented in the intestine on a daily basis for absorption . The effde novo synthesis of cholesterol occurs in all cells in the body. However, the liver represents the main site for cholesterol synthesis and storage . HDL is taken up by hepatocytes via the scavenger receptor B1 (SR-B1)  Figure .The expression of genes responsible for cholesterol transport and metabolism are tightly regulated by coordinated actions of transcription factors. For example, the decrease in the level of cellular cholesterol activates the ER membrane-bound transcription factor Sterol regulatory element-binding protein isoform 2 (SREBP-2) that induces the expression of HMGCoAr and LDLr . On the The interest in understanding the relationship between cholesterol metabolism and the development of NAFLD and NASH was incited by observational studies linking liver damage with the risk for the development of cardiovascular disease (CVD) . In factIt should be noted that animal species have remarkable differences in cholesterol metabolism and respond differently to cholesterol rich diet. In this regard, it is well-established that rabbits have features of cholesterol metabolism that are closer to those in humans . For exaAn interesting observation was made in wildtype mice (but not in the transgenic mice models of hypercholesterolemia) showing that high cholesterol in the diet was essential to elicit steatohepatitis and fibrosis after 30 weeks of feeding, whereas high fat diet alone failed to produce the same degree of liver injury . This roBeside the studies in animal models, the results of a landmark study in humans also supported the role of cholesterol in NAFLD/NASH. Puri et al.  showed hRecent studies investigated the molecular mechanisms underlying the toxic effects of high cholesterol in the liver. The findings of Mari et al.  providedThe accumulation of free cholesterol in NAFLD may occur due to an upregulation in the input pathways or a decrease in the elimination of cholesterol. Studies showed that the expression of HMGCoAr are increased in patients with NAFLD/NASH . There iWith respect to cholesterol metabolism as it relates to NAFLD/NASH, miR-34a levels were shown to be elevated in patients with NAFLD/NASH causing a decrease in hepatic NAD-dependent deacetylase Sirtuin1 with subsequent dephosphorylation and an increase in HMGCoAr . The rolThe expression of SREBP2 transcription factor was also increased in patients with NAFLD/NASH . Since SBeside the increase in cholesterol synthesis, changes in the pathways involved in the elimination of cholesterol were also noted in patients with NASH. Among these observations is the decrease in the expression of CYP7A1 implicating reduced bile acid synthesis from cholesterol . Also, aWith respect to dietary cholesterol and liver disease in humans, an epidemiological study suggested that dietary cholesterol is an independent risk factor for liver cirrhosis and hepatic cancer . These sAccording to current guidelines, decreasing the levels of plasma cholesterol to stringent low levels is highly recommended in patients with high risk for CVD , 48. PatStatins, the inhibitors of HMGCoAr, are the widely used drugs to lower plasma cholesterol . It is wThe effects of statins on several aspects of liver injury was shown in animal models . StatinsBlocking the absorption of bile acids eliminates the negative feedback inhibition on their hepatic synthesis and promotes cholesterol degradation . ASBT meStudies showed that the inhibitor of cholesterol absorption ezetimibe reduces plasma cholesterol and decreases the risk of CVD when used alone or in combination with statins , 68. EarDisturbances in cholesterol metabolism contribute to the pathophysiology of NAFLD/NASH. An increase in cholesterol synthesis and a decrease in the pathways responsible for the elimination of cholesterol lead to accumulation of free cholesterol in the liver. The toxicity of high cellular levels of cholesterol in hepatocytes is one of the major factors causing inflammation and fibrosis leading to liver damage. The pathways involved in cholesterol metabolism are potential targets for the treatment of NAFLD/NASH. One challenging area is the complex nature of the processes involved in cholesterol homeostasis. For example, cholesterol absorption exhibits wide interindividual variations that may explain the conflicting results when evaluating the efficacy of cholesterol lowering drugs in the treatment of NAFLD/NASH. Such variations evoke the need for precision medicine approaches and individualized treatment. It is possible that individuals with naturally occurring low efficiency of cholesterol absorption may not benefit from the use of cholesterol absorption blocker ezetimibe. It will be interesting in future studies to stratify patients into relevant subgroups in a rigorous manner and take into consideration the inter-individual variations in cholesterol metabolism when assessing the outcome of cholesterol lowering drugs in the treatment of NAFLD/NASH. Precision medicine approaches necessitate the development of novel and simple methods to directly measure dynamic processes such as cholesterol absorption when individualized therapeutic interventions are to be considered for NAFLD/NASH treatment.WA and PM wrote the initial draft. RG and SS edited the initial manuscript. PM and RG made the figure. RG and WA made the table. PM, RG, SS, and WA edited and approved the final draft. All authors contributed to the article and approved the submitted version.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.


In recent decades, the field of neuroimaging has experienced a surge of popularity and innovation which has led to significant advancements in the understanding of neurological disease, if not immediate clinical translation. In the case of Down's syndrome, a complex interplay of neurodevelopmental and neurodegenerative processes occur as a result of the trisomy of chromosome 21. The substantial potential impact of improved clinical intervention and the limited research under-taken to date make it a prime candidate for longitudinal neuroimaging-based study. However, as with a multitude of other multifaceted brain-based disorders, singular utilization of lone modality imaging has limited interpretability and applicability. Indeed, a present challenge facing the neuroimaging community as a whole is the methodological integration of multi-modal imaging to enhance clinical understanding. This review therefore aims to assess the current literature in Down's syndrome utilizing a multi-modal approach with regards to improvement upon consideration of a single modality. Additionally, we discuss potential avenues of future research that may effectively combine structural, functional and molecular-based imaging techniques for the significant benefit of the understanding of Down's syndrome pathology. Down syndrome (DS) is the leading genetic cause of intellectual disability, with an approximate incidence of 1 in 750 live births . The pro18F]-fluorodeoxyglucose-PET (FDG-PET) and gray matter atrophy and white matter dysfunction as seen with structural T1-weighted MRI, resting-state connectivity differences  within a longitudinal design would be useful to unravel their relative roles, sequence, and causal relationships in the context of DS. To this end, large-scale initiatives such has ABC-DS have begun and the research community would be to synthesize the vast amounts of data meaningfully to help us understand better the neuropathological processes and clinical manifestations.To continue advancement of understanding in the field of Down's syndrome neurodegeneration, it is key that recent innovations in neuroimaging technology are harnessed. As integration of more than one imaging modality leverages significantly more pathology-relevant information that standard methodologies, it is of importance that approaches for doing so are put forward and discussed. In this brief review, we highlight prominent existing research that utilizes such multimodal neuroimaging methods and consider future directions in a methodological context.in vivo evidence using [11C]-PiB PET imaging (11C]-PiB PET study of presenilin-1 (PS1) mutation carriers  from [11C]-PiB PET imaging has been validated by Mak et al.  is a non-invasive olecules . Howeverolecules , 29. GivThe intersection of the clinical understanding of brain pathology and technological innovation in neuroimaging has yielded significant progress in the fields of psychiatry and neurology. However, single modality imaging is inherently limited in the information it can reveal, restricting the understanding of complex and multifaceted disease processes. The complexity problem of neuroimaging datasets in neurological study and the dynamic nature of pathology is difficult to address. The successful and meaningful integration, therefore, of multiple brain imaging modalities is key to clinical progress, whether that be rooted in biomarker identification or translation to therapeutics.Machine learning is emerging as a significantly useful technique which can both reduce and utilize the high dimensionality of neuroimaging data . Thus, sSupervised machine learning algorithms are commonly applied using either a classification or regression approach, where the outcome variable of interest is either binary or continuous, respectively , 32. The0 magnetic field and the anisotropy of water diffusion along multiple magnetic gradient b-vectors, respectively -PET, broad neurotransmitter and metabolite levels can be extracted from spectroscopy methods and brain structural analyses can examine how regional volumetrics and form associate with neurocognitive measures. The synergistic advantages of combination of these techniques mean that longitudinal imaging studies are valuable for the understanding of pathology and trajectory of disease. Building the evidence base of the development of neuropathology in DS-AD is crucial therefore, not just for more efficient diagnoses, but for identifying pertinent disease stages for effective intervention, potentially modifiable risks and mechanisms or patterns of brain alteration that can be therapeutically targeted. Gaining such knowledge as the degree of involvement of the noradrenergic and cholinergic systems in DS-AD through regional analyses of specialized brain nuclei is one example of how this may be achieved. In this review, we also put forward potential methodological approaches for future research in the field, with the aims of demonstrating that novel advancements in how data is combined can yield pertinent insights into neuropathology and begin to translate research more effectively into patient benefit.SB and EM contributed equally to manuscript writing and conception. SZ contributed to manuscript conception and provided manuscript feedback. All authors contributed to the article and approved the submitted version.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.


While caregivers endure considerable challenges, including potentially deleterious effects on their own well-being, the possibility of positive outcomes for caregivers, such as feeling rewarded and satisfied, has been recognized in scholarly research as well. Caregiving outcomes can be complicated by different aspects of caregiving experiences. Particularly, the Positive Aspect of Caregiving (PAC) scale covers four main positive aspects including caregiving personal gains, motivation for caregiving role, caregiver satisfaction, as well as self-esteem and social aspect of caring. The objective of this study is to summarize the research findings based on the PAC scale and further improve the understanding of the positive experience perceived by caregivers. A systematic literature review was conducted to identify the existing evidences. This systematic review identified empirical research studies written in English focusing on a PAC scale that were published in a peer-reviewed journal between 2004 and 2018. Systematic search was carried out within 10 databases. After careful review of 193 abstracts yielded from the databases, 38 journal articles were identified to have used the PAC scale. Analysis of the selected literature provides four themes that how PAC has been used. The themes are to measure caregiving outcomes, test the effect of caregiver program intervention, complement other caregiving outcome scales, and test the validity in other languages and countries. This systematic review highlights the importance of taking into account of the positive experience of caregiving and further to promote it in a way of buffering the negative outcomes of caregiving.


Endovascular procedures with liquid embolic agents such as ethylene-vinyl alcohol (EVOH) copolymers are indicated before surgical treatment of cervical paraganglioma. Consequently, these agents are now available as low viscosity formulations, one of which is Squid 12, which are demonstrating superior vascular penetration. Cases of facial paralysis secondary to embolization of cervical vascular lesions with classic embolic agents have been reported in the English literature, however, this complication has not been described with new generation options such as Squid 12.We describe the case of a 43-year-old patient with a left neck carotid paraganglioma. Embolization was performed under general anaesthesia before surgical excision. In the immediate postoperative period, the patient developed total left facial palsy. Since the imaging tests (Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)) and neurological examination showed no involvement of additional cranial nerves (CN), we hypothesise that the main cause of this complication is ischemia of the vasa nervorum of CN VII secondary to embolization. Almost six months later, the patient continues to present total facial paralysis , and palsy of the left CN X and XII as a complication secondary to surgical resection of the paraganglioma.This case is relevant since it is the first clinical case of permanent facial paralysis secondary to embolization with Squid 12. The choice of embolic agent for embolization of vascular head and neck tumours is challenging since the vascular patterns of tumours that are optimal candidates for this agent have not yet been defined . HoweverSquid®  is a copolymer of EVOH dissolved in a DMSO (dimethyl sulfoxide) solution with suspended micronized Tantalum powder for radio-opacity. While Squid 18 has similar properties to Onyx®, Squid 12 is innovative in terms of viscosity. A less viscous product, Squid 12 is more fluid than other agents. Studies show that this property enhances penetration of the tumoral parenchyma and diffusion of the embolic agent in parts of the tumour further from the puncture site –5. AlthoWe describe the case of a 43-year-old woman diagnosed with cervical paraganglioma as a casual finding in computed tomography. Her medical history included sinusopathy complicated by sinus thrombosis and bilateral optic neuropathy with no clinical signs of effect on the facial or other cranial nerves. A laryngeal examination by the otolaryngologist two months earlier was normal, revealing no abnormal findings. The CT image shows a 32x26x41mm carotid paraganglioma  with normal sensitivity. No other loss of neurological function was detected.The stroke code was activated in response to the clinical examination and vascular procedure performed. Computed tomography(CT)perfusion, and an MR angiography of the supra-aortic vessels Figs.  and 3 shThe surgeon completed the resection of the paraganglioma three days after the embolization, but could not avoid damaging the vagus nerve (CN X), resulting in recurrent left laryngeal nerve paralysis. The surgery also affected CN IX, XI, and XII, eliminated the gag reflex, caused hypoesthesia of the left side of the face and pharynx, velopalatine asymmetry and motor dysfunction of the tongue. Five days after the operation, the patient still presented Grade V left-side facial paralysis and the left side of the vocal chords were paralysed with signs of acute laryngeal compensation. However, the motor tone of the tongue had recovered completely. Episodes of aspiration were observed in the volume-viscosity swallow test (V-VST). Rehabilitation and inserting a nasogastric tube as an initial measure, although finally, because of the deteriorating situation, it was decided that our Dysphagia Unit should perform a percutaneous gastrostomy.The patient continues to suffer from facial paralysis, but to a lesser degree on the House-Brackmann scale (IV): lack of lip seal, facial asymmetry at rest and poor facial movements, without synkinesis.MRI performed in the immediate postoperative period Fig. , showed Facial palsy is a rare complication in patients undergoing arterial embolization. There is a theoretical estimated 6% risk of harbouring an anatomical vascular pattern that may expose the facial nerve to greater risk during embolisation , 3–5. FuSudden onset facial palsy subsequent to an endovascular procedure should be treated as a major complication. All patients should be apprised of this risk before undergoing this type of procedure because of its psychological and social impact. Squid 12 is considered a safe liquid embolic agent for this type of procedure.We have described an initial case of permanent facial paralysis after the use of Squid 12 when embolising vascular tumours of the head and neck. We believe that due to the complex vascular anatomy of the area, it is likely that small vasa nervorum were occluded when diffusing the embolizing agent, since there were no difficulties during or after the technique. This vasa nervorum occlusion could have happened on the one hand, in the intrapetrosal course from the Fallopian canal, where the facial nerve is supplied by the petrous branch of the middle meningeal artery and by the stylomastoid branch of the occipital artery, which sometimes originates directly from the external carotid; and on the other hand, in the extrapetrosal portion of the facial nerve, that first receives irrigation from branches of the occipital and posterior auricular arteries at the base of the skull, and subsequently at the level of the parotid gland and outside of it, where vessels come from the superficial temporal for the temporofacial trunk and from the facial for the cervicofacial trunk .If we compare the Squid 12 with the Onyx, are very similar in terms of composition. However, that lower viscosity described in the Squid 12 literature, can favor penetration in all vascular pedicles and their more distal branches, affecting irrigation vascular of the facial nerve in this case. The persistence of the nerve injury could also be favored by postoperative changes on MRI Fig. .This case shows that cranial nerve palsy is a possible complication of the procedure even with the new embolic agents such as Squid 12, therefore an accurate risk-benefit assessment is always necessary before the treatment. In our opinion, further studies are required to assess the risk-benefit ratio of preoperative embolization with new liquid embolic agents in asymptomatic vascular head and neck tumours.


A double aortic arch (DAA) with atresia is an uncommon cause of a symptomatic vascular ring resulting in trachea-esophageal compression. An atretic double aortic arch can resemble the right aortic arch with a mirror image branching pattern or the right arch with an aberrant left subclavian artery depending upon the level of atresia. The double aortic arch with atresia is difficult to detect on pre-surgical computed tomography angiography or magnetic resonance angiography due to a lack of contrast in the obliterated arch segment. Differentiation of a double arch with atresia from the right aortic arch is vital as an atretic double arch is a form of the complete vascular ring while the right aortic arch may or may not be symptomatic. Knowledge of some key imaging features can help distinguish these entities. In this case report, we discuss an uncommon case of a double aortic arch with atresia between the left common carotid and left subclavian artery. We also describe its close mimics, their embryological basis, and ways to differentiate it from the right aortic arch. Vascular rings are a rare form of aortic arch anomaly resulting in trachea-esophageal compression and represent 1%-3% of all congenital heart diseases . DAA witA two-year-old male child with a history of noisy breathing presented with a concern of murmur heard on clinical examination. A grade I/II murmur was heard on the left sternal border. Transthoracic echocardiogram was limited due to a lack of patient cooperation with incomplete visualization of the aortic arch but showed mild flow turbulence in the aortic arch and dampened flow in the descending thoracic aorta. Pulsatile flow was seen to the left of the left pulmonary artery that could not be fully evaluated on echocardiogram. The child underwent computed tomography angiography (CTA) of the chest for further evaluation. Non-gated CTA of the chest (DLP 43 mGy*cm) was performed in high-pitch (FLASH) mode on the Siemens dual-source scanner . CT showed a relatively symmetrical appearance of both common carotids and subclavian arteries (four-vessel sign) just above the level of the aortic arch Figure . There wThe reconstructed three-dimensional model , and diverticular outpouching from the descending thoracic aorta helped suggest that imaging was highly suggestive of DAA with atresia between the LCCA and LSCA. The vascular ring was completed by the dominant aortic arch on the right, ascending aorta anteriorly, retroesophageal aortic segment posteriorly, and an atretic segment of the left aortic arch on the left side. Due to the concern of complete vascular ring and symptoms, the child underwent surgical repair via left thoracotomy, and an obliterative segment was found between LCCA and LSCA, confirming the atresia as seen on CTA chest. The child was successfully treated by the division of the atretic left-sided aortic arch.The embryological basis of normal aortic arch formation is critical to understand the complex arch anomalies. Edwards’ hypothetical DAA model helps better understand the aortic arch malformations Figures -3B and hDAA is formed when there is the persistence of the bilateral fourth branchial arches, one on each side of the trachea and the esophagus. Each aortic arch gives rise to the respective right and left common carotid and subclavian arteries. Both arches join to form a single descending aorta, which is commonly located to the left of the spine. Less often, the descending aorta is seen on the right of the spine and rarely is midline in location. The ductus, if present, is left-sided but rarely can be right-sided or bilateral . ClinicaImagingEchocardiography is often the initial investigation performed for the evaluation of suspected vascular ring. However, it is operator dependent and is often limited if the child is small and uncooperative . CatheteDouble aortic arch without or with atresiaIn the majority of patients, both aortic arches are patent, and CTA with three-dimensional reconstruction can easily visualize a double aortic arch if both arches are patent. In general, the right aortic arch is dominant and is cephalic relative to the left arch. However, both arches may be equal in caliber, and less commonly, the left arch may be dominant .Rarely, there may be atresia of a segment of one aortic arch, which most commonly involves the left side . The atrOn axial CTA images, the presence of four aortic arch branches  in a symmetric trapezoidal fashion seen just above the level of the aortic arch is a highly sensitive sign of DAA Figure  17]..17].Secondly, the first aortic branch, as seen on axial images, is more posterior in its initial course in patients with atretic DAA Figure . TetheriIn contrast, in the right aortic arch, no symmetric pattern of arch branches is seen Figure  with theMimics of the atretic double aortic archDAA With Atresia Distal to the Left Subclavian ArteryIn these patients, the atretic DAA Figure , Video 3DAA With Atresia Between the Left Common Carotid and Left Subclavian ArteriesHere, the atretic DAA anatomy Figure  resembleDAA With Atresia Between the Ductus and Left Subclavian ArteryIn such patients, atresia involves the left dorsal aorta segment between the left ductus and left subclavian arteries Figure . This apManagementDAA is managed by the surgical division of the non-dominant arch in patients with respiratory or esophageal symptoms . 3D imagAn atretic double aortic arch is an uncommon cause of a complete vascular ring. An echocardiogram is frequently limited in assessing the atretic double aortic arch and its branches due to the suboptimal window and dependence on patient cooperation. Non-gated CTA with three-dimensional visualization is an excellent technique for the visualization of atretic DAA and differentiates it from its close mimics. A symmetric four-vessel sign at the thoracic inlet, posterior course of a patent segment of the atretic left arch, and presence of a diverticulum at the descending aorta are the diagnostic clues that differentiate atretic DAA from the right aortic arch with mirror image branching or the right arch with an aberrant left subclavian artery.


Sepsis is the leading cause of death worldwide. Timely administration of antibiotics is recognized as the cornerstone in the management of sepsis. However, inappropriate use of antibiotics may lead to adverse effects and the selection of drug-resistant pathogens. Microbiological cultures remain the gold standard to diagnose infection despite their low sensitivity and the intrinsic delay to obtain the results. Certain biomarkers have the benefit of rapid turnover, potentially providing an advantage in timely diagnosis leading to accurate treatment. Over the last few decades, there is an ongoing quest for the ideal biomarker in sepsis. Procalcitonin (PCT), when used alone or alongside additional clinical information, has shown to be a promising tool to aid in the diagnosis and management of patients with sepsis. In February 2017, the Food and Drug Administration (FDA) approved the use of PCT to guide antibiotic treatment in lower respiratory tract infections and sepsis. Despite a good negative predictive value for bacterial infection, the utility of PCT-guided antibiotic initiation is conflicting at best. On the other hand, the use of PCT-guided antibiotic discontinuation has shown to reduce the duration of antibiotic use, the associated adverse effects, and to decrease the overall mortality.The current review discusses the history and pathophysiology of procalcitonin, synthesizes its utility in the diagnosis and management of sepsis, highlights its limitations and compares it with other biomarkers in sepsis. Sepsis, the leading cause of death globally, has an estimated incidence of 18 million cases per year worldwide and a mortality rate of approximately 30%.Culture methods with microbial isolation continue to be the gold standard for diagnosis of infection despite their low sensitivity. Blood cultures are negative in up to two-thirds of cases and cultures from all sites are negative in up to one-third of sepsis cases.The intracellular precursor of calcitonin, currently known as procalcitonin (PCT), was first discovered in 1975 during the study of calcitonin biosynthesis in chicken ultimo-branchial glands.In healthy individuals, PCT is produced in the thyroid C-cells, cleaved from pre-procalcitonin by an endopeptidase in the endoplasmic reticulum Figure . PCT is 9During inflammation and sepsis, the production of PCT follows an entirely different pathway Figure , details12PCT has been increasingly used in the management of sepsis. Patients with higher PCT levelsPCT is an intriguing biomarker for the early diagnosis of sepsis in critically ill patients. Several studies have supported the use of PCT for making a diagnosis of sepsisA meta-analysis22It is important to note that these studies compared PCT to a clinical diagnosis of sepsis; therefore, the results could be confounded by clinician variation. Moreover, the lack of a uniform cut-off level of PCT used for the diagnosis of sepsis could potentially explain the difference in the stated results. Despite growing evidence supporting the utility of PCT, its use as a diagnostic tool in sepsis remains questionable because of relatively low sensitivity and lack of a precise cut-off level.A randomized controlled trial looking at PCT guided initiation of antibiotics in critically ill patients did not show effectiveness in decreasing the total antibiotic days.Several studiesThe Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guidelines for the treatment of Community-Acquired Pneumonia (CAP)As previously discussed, PCT level drops rapidly (50% in 24 hours)PCT guided antibiotic discontinuation did not show a mortality benefit when a low-level PCT cut-off (1 ng/dl) was used.Clostridium difficile diarrhea, the emergence of antibiotic resistance, or overall mortality.Multiple other studies, however, have shown that PCT guided antibiotic protocol reduces cumulative antibiotic exposure in patientsDe Jong et al.The IDSA/ATS guidelinesWhile the mortality benefit of a PCT guided strategy to discontinue antibiotics is questionable, there is enough data to suggest that PCT has shown to decrease antibiotic exposure and antibiotic-related adverse effects. Based on the available data, we feel strongly that PCT can be incorporated into the management of sepsis and used in making the decision to discontinue antibiotics in appropriate patients.We have limited data on direct comparison between PCT and presepsin. While PCT has a higher diagnostic accuracy than presepsinPresepsin has a pooled sensitivity of 0.88, while that of PCT is 0.75. The pooled specificity of presepsin is 0.58 compared to 0.75 for PCT.C-Reactive Protein (CRP) is an acute-phase reactant and a sensitive marker for inflammation and tissue injury that cannot differentiate infective from non-infective causes of inflammation. The slow variation of CRP levels constitutes another major limitation compared to PCT. Therefore, an otherwise normal CRP level could introduce an unacceptable delay in starting appropriate antibiotic treatment, ultimately affecting mortality.Compared to CRP, PCT has a better predictive value for admission to the special care unit and duration of intravenous antibiotic use.60Despite being the most accepted biomarker in sepsis, PCT is far from being an ideal biomarker. PCT has many limitations that should be taken into consideration when incorporating PCT in the management of a potentially septic patient.Falsely low PCT in localized infections like cellulitis, appendicitis, abscess and empyema can be misleading.Serum levels of PCT increase in patients with deranged renal function. Considering the high incidence of renal failure in patients admitted to hospital and critical care units, the utility of PCT might be limited. While some studies report that PCT can still be used in patients with renal failureSerum PCT is a promising biomarker for early detection of bacterial sepsis with a good negative predictive value for bacteremia. The current evidence supports PCT-guided discontinuation of antibiotics, while the data behind PCT-guided initiation of antibiotics is not as strong.The current studies addressing the utility of PCT in sepsis management are conflicting as patient characteristics and clinical settings vary markedly among them. The use of different PCT cut- off levels as well as different algorithms for PCT guidance make the interpretation even more difficult. However, most of the studies have shown that PCT guidance results in lower antibiotic exposure and antibiotic-associated adverse effects without compromising clinical outcomes. Nonetheless, PCT should always be used in conjunction with clinical findings.


Introduction. The objective of this study was to evaluate a surgical technique and to present the results of delayed reconstruction of palatomaxillary defects using fibula free flap (FFF). Methods. A review was conducted for nine patients who underwent palatomaxillary reconstruction using FFF. Primary disease, type of reconstruction, defect area, fibula segment length and number of osteotomies, radiotherapy, and implant installation after FFF reconstruction were analyzed. Results. All nine patients underwent delayed reconstruction. The fibula shaft was osteotomized into two segments in seven patients and three segments in one patient with bilateral Brown’s revised classification IV/d defect. One case was planned by using a computer-aided design computer-aided manufacturing (CAD/CAM) system with a navigation system. The mean length of the grafted fibula bone was 68.06 mm. Dental implant treatment was performed in six patients. Six patients received radiation therapy, and there were no specific complications related to the radiation therapy. In one case, the defect was reconstructed with FFF flow-through from a radial forearm free flap. Conclusion. This clinical study demonstrated that the fibula flap is an ideal donor-free flap in a palatomaxillary defect. Delayed reconstruction using an FFF can reduce the complication and failure rates. Oral and maxillofacial defects after surgical resection of malignant tumors frequently involve the maxilla with the palate. This kind of defect can also be a result of benign lesion or trauma and include the lining mucosa, teeth, and bone. Palatomaxillary defects sometimes extend over the midline and, if not adequately reconstructed, can result in poor esthetic and functional outcomes. The defects are problematic not only for the patients in functional and psychological aspects but also for the surgeons who try to achieve the ideal outcomes. Restoration of these defects would be a great challenge for clinicians.The maxilla is a multifunctional bony structure that provides mechanical support to the midfacial area and contributes to esthetic appearance. It provides mechanical support to the orbit and bony framework for the maxillary dentition . In addiThere are several methods to restore palatal and maxillary defects ,3,4. PreA considerable number of surgical techniques has been used to reconstruct palatomaxillary defects. In previous studies, contouring of various soft tissue and bony free flaps including fibula, rectus abdominis, scapula, anterolateral thigh, radial forearm, and latissimus dorsi gained popularity for maxillary reconstruction . All of Reconstruction of maxillofacial defects with the fibula free flap is a well-established technique ,11. FibuStudies have shown excellent outcomes of dental implant placement in the fibula after reconstruction with the fibula free flap ,13,14,15The purpose of this study was to evaluate the outcomes of palatomaxillary defect reconstruction using the fibula free flap. The specific aim of the study was to show that three-dimensional model simulation and preoperative planning is an effective method to refine the procedure, to shorten the surgical time, and to predict postsurgical outcomes.All of the records were reviewed for the patients who underwent reconstruction of midfacial defects treated in the maxillofacial surgery department of Seoul National University Dental Hospital. Institutional review board approval was obtained for this review (IRB 081/07-14). An author performed a retrospective review of medical record in all patients who received the reconstruction of midfacial defects. Nine consecutive cases of the fibula free flap with maxillofacial reconstruction were reviewed.The 3D-printed model was manufactured in all of cases for cosmetic and functional reconstruction procedure in order to restore supportive function of midfacial structures and to apply the dental implants and further prosthetic rehabilitation. This procedure was performed in the following steps: analysis of the patient’s CT DICOM data; simulation of the obtained data into a three-dimensional (3D) image; and printing of the 3D model including the defect area with 3D printer . The 3D ®, Munich, Germany), which facilitated fabrication of the customized device to provide the patient with midfacial reconstruction. DICOM data of CT was imported into digital planning program  and aligned during the planning process. The alignment of the dataset allowed a comparison between both sides of the patient in one view. The segmentation and mirroring of objects was the most time-consuming step when using digital planning software, where the objects were segmented accurately within 3 h. The mirrored data could be manipulated and positioned according to given anatomical structures of the affected side. The STL export system of the program allowed objects and anatomical structures to be exported for the production of patient-specific osteotomy guide or rapid prototyping models. The pre-shaped segment and osteotomy guide were manufactured using a 3D printing system. The fibula bone was designed and cut using the osteotomy guide during operation, and the navigation system was used to enhance the accuracy of placement of the fibular graft [One case was planned by computer-aided design/computer aided manufacturing (CAD/CAM) system with navigation system . ®, Munich, Germany) was utilized with a special template technique and showed promising results for computer aided design/computer aided manufacturing (CAD/CAM) applications in reconstructive surgery (The fibular bone was osteotomized into two segments in seven patients and three segments in one patient with bilateral Brown’s revised classification IV/d defect. The defects on the midfacial area were on the right side in 4 patients and on the left side in 5 patients. At surgery, the mean length of fibular bone was 68.06 mm . Of all  surgery . Of the  surgery . These iMaxillofacial trauma or tumor ablation often results in severe defects in the palatomaxillary area, and such defects require soft tissue, bone, and implant placement for the adequate restoration of structure and function . Oral anThe goals of reconstruction in palatomaxillary defect includes proper oronasal separation, provision of the alveolar arch, preservation of speech and occlusion, construction of structural framework of the midface, and provision of the midfacial projection while maintaining the nasal airway patency . Debate Fibula free flap was used for palatomaxillary reconstruction in this study. The use of the fibula free flap for palatomaxillary reconstruction has some advantages. The fibula bone provides 25 cm of bone in maximum for the reconstruction and the availability of shaping it. Its periosteal vascularization allows multiple osteotomies for esthetic reconstruction of palatomaxillary defect . The bonIn approximating fibula free flap to the defect, orientation of the vascular pedicle, the skin paddle, and the septal perforator must be considered in the preoperative procedure. In a cross-sectional view of the fibula free flap, the outline of fibular bone is triangular shape. The posterior intermuscular septum and the skin paddle are located at one of the angles. Septal perforators can be seen along a side between the angles, with the perforator coursing along the septum to the skin island . The sidThe preoperative procedure involves the CAD/CAM system with navigation system in order to prepare device for assistance in the surgery ,29. The Maxillofacial trauma or tumor ablation often results in compound defects in the maxillofacial region, and such defects require bone, soft tissue, and dental implants for the proper restoration of form and function . The sufDental implants would reconstruct the defects to improve the nutritional supply and psychological condition of patients after maxillofacial surgery. The implants are usually placed through the grafted skin paddle to restore function and esthetics after the reconstruction ,35. ByunSix patients received radiation therapy. Free flap operation in patients who undergo radiotherapy is arduous as it involves dissecting easily nicked vessels and atrophied tissues. These factors are likely to lead to vascular damage and excessive bleeding during surgery. According to previous studies, free flap reconstruction of irradiated maxillofacial defects showed a lower success rate than that observed for non-irradiated defects ,38,39. IThis clinical study demonstrates that fibula flap is an ideal donor-free flap in palatomaxillary reconstruction because of its length, thickness, and bone uniformity, which provide an ideal support for the adequate rehabilitation. The flow-through forearm radial flap not only serves as the vascular bridge to midface reconstruction but also provides sufficient soft tissue to cover the intraoral defect. The use of a CAD/CAM system and preoperative surgical planning is an effective method to refine reconstruction surgery, to enhance clinical outcomes, and to shorten operation time. Moreover, delayed reconstruction of the palatomaxillary defect using a fibula free flap can reduce complications and failure rate, especially in patients who have received radiotherapy.


Eight human thoracic spine specimens (C7-L1) including the rib cage were loaded with pure moments of 5 Nm in flexion/extension, lateral bending, and axial rotation while tracking the motions of all functional spinal units. Specimens were tested stepwise in four different conditions: (1) In the intact condition, (2) after cutting all anterior rib-to-rib connections, (3) after partitioning the polysegmental specimens into monosegmental specimens, and (4) after removing the ribs in the monosegmental condition. Significant increases of the range of motion (p < 0.05) were especially found at the segmental levels of the upper half of the thoracic spine in all motion planes and for all resection steps, particularly in axial rotation, while the stabilizing effects of the structures decreased in inferior direction. Partitioning of polysegmental specimens into monosegmental specimens primarily affected the stability in lateral bending, while the effects of resection were generally lowest in flexion/extension. Presence of the ribs, anterior rib cage integrity, and segmental length all affect the thoracic spinal stability and have therefore to be considered in the calibration process of numerical models of the thoracic spine and rib cage.The effects of segmental length as well as anterior rib cage and costovertebral joint integrity on thoracic spinal stability have not been extensively investigated, but are essential for the calibration and validation of numerical models of the thoracic spine and rib cage. The aim of the study was to quantify these effects by  In case of the thoracic spine, however, these factors are not well-investigated and need to be considered separately due to the specific characteristics of the thoracic spinal morphology and the presence of the rib cage. Numerical models of the thoracic spine and rib cage can be used to simulate these effects in the treatment of specific thoracic spinal pathologies, such as scoliosis and hyperkyphosis. For the generation of reproducible and realistic results, numerical models of the thoracic spine and rib cage have to be calibrated and validated , preferain vitro studies in order to create data for the calibration and validation of numerical models of the lumbar spine  including the intact rib cage were obtained from middle-aged male donors . The speBiomechanical testing was performed using a well-established universal spine tester  allowing®, Zuchwil, Switzerland) and a scalpel to create anterior rib cage disconnections between the single spinal segments. In the third step, the polysegmental specimens were separated into the six thoracic spinal motion segments T1-T2, T3-T4, T5-T6, T7-T8, T9-T10, and T11-T12 by cutting the respective intervertebral disks and spinal ligaments using a scalpel. The monosegmental specimens were again embedded in PMMA and biomechanically tested afterward. In the fourth step, testing was performed after removing the ribs by carefully cutting the stabilizing ligaments at the costovertebral joint using a scalpel.Thoracic spinal stability was tested stepwise in four different specimen conditions : in the Data obtained from biomechanical loading and motion analysis were merged and evaluated regarding range of motion (ROM) and neutral zone (NZ) using a custom-written Matlab script . Using Microsoft Excel , data were compiled and prepared for statistical analysis, which was performed using the statistics software SPSS .n = 8, cumulated data are presented as median and range. Changes in the median ROM between single sequential testing steps were checked for significance using the non-parametric Friedman test for multiple paired samples, since non-normal distribution was expected based on the low sample size. The significance level was set to α = 0.05.Due to the overall low, but for biomechanical studies usual sample size of The use of human thoracic spine specimens was approved by the Ethical Committee Board of the University of Ulm, Germany, on November 2014 (No. 302/14). The specimens were obtained from an accredited and ethically approved body donation program .p < 0.05) of the ROM of the entire thoracic spine (T1-T12) was detected in all three motion planes , the flexibility also increased after each resection step in all three motion planes . TransveRegarding the isolatedly viewed flexibility of the single thoracic functional spinal units, significant effects of the resection steps on the ranges of motion were especially found in the upper thoracic spinal section between T1-T2 and T5-T6 in all three motion planes . In partNeutral zone values of the single thoracic spinal motion segments generally exhibited too high variability for conclusive statistical analysis, particularly in the polysegmental setup. Overall, NZ values were highest in the polysegmental state after transversal cutting of the sternal and cartilaginous rib-to-rib connections in flexion/extension and lateral bending, respectively, while increasing almost constantly after every resection step in axial rotation. The results for all ROM and NZ values, together with statistical analysis values, are retrievable from the in vitro studies on the thoracic spine and the clinical application of novel treatment methods, data on these stabilizing effects are essential. Therefore, this study aimed to quantify possible effects of anterior rib cage disconnection, reduction of spinal length, and removal of the ribs on the segmental stability of the thoracic spine.The stabilizing effect of the single rib cage structures is still not fully understood. For the highest possible accuracy of numerical model calibration and validation, but also regarding the interpretation of in vitro studies investigating the effects of median sternotomy (The results of the present study indicate that the upper rib cage section primarily affects thoracic spinal stability, while the stabilizing effect of the rib cage generally decreases in inferior direction. This can be explained by the more rigid anterior connection of the ribs in the upper half of the bony thorax due to the sternal complex, while becoming more flexible in the lower half because of solely cartilaginous connections in case of the false ribs as well as missing connections in case of the floating ribs. This effect was especially seen after removal of the ribs, showing significant ROM increase in the motion segments T1-T2 to T5-T6, but not in the motion segments T7-T8 to T11-T12. Therefore, it can be assumed that the integrity of the sternal complex represents a major factor in the stability of the thoracic spine, which corresponds to the results of previous ernotomy , transveernotomy , and traernotomy  on thorain vitro studies investigating the mechanical contribution of the rib cage on thoracic spinal stability (The highest impact of rib cage resection on thoracic spinal stability was generally found in axial rotation movement, especially in the upper rib cage half and after transversally cutting the sternal and cartilaginous rib-to-rib connections. This indicates that the rib cage mainly stabilizes the thoracic spine in the transversal plane, which was also detected in previous tability . This efin vitro study investigating the influence of specimen length on the ROM in the lumbar spine (in vitro studies using polysegmental (Significant effects of segmental length were mainly found in lateral bending movement, indicating that especially sideward bending resistance depends on spinal structures which extend across multiple segments. From a biomechanical point of view, laterally positioned ligaments, such as the intertransverse or costotransverse ligaments, could account for higher spinal stability due to the increased lever arm in the transversal plane, while their stabilizing effect is probably enhanced by increasing spinal length and intact costovertebral joints. In general, the effect of segmental length on thoracic spinal stability corresponds with findings of a previous ar spine . The desegmental  as well egmental  experimein vivo as well as in vitro studies regarding qualitative intersegmental motion distribution along the thoracic spine. Quantitatively, the ranges of motion were slightly lower using the polysegmental setup and slightly higher using the monosegmental setup compared to average ROM data summarized in a literature review on thoracic spinal motion segments including multiple different in vitro test setups and tested segmental levels (in vitro study investigating the flexibility of all thoracic spinal motion segments for the validation of thoracolumbar numerical models (in vitro studies on the lumbar spine, while the analyzed studies in the literature review of in vivo studies in flexion/extension (in vitro. Pure moment loading therefore seems to represent a limited, however adequate approach for numerical model calibration and validation of the thoracic spine and rib cage. Although the simulation of muscle forces and body weight would probably represent more physiological loading conditions, thoracic spinal stiffness is significantly decreased in vitro and further boundary conditions are created for the numerical models (in vivo situation (in vitro and in silico studies should also include the effect of compressive loading in addition to sole pure moment loading in order to generate realistic biomechanical behavior.Comparing the results of the present study with data from previous studies, the segmental ranges of motion were overall similar to the results of l levels , while bl models . These qxtension , lateralxtension , and axixtension , the resl models . Moreoveituation . Neverthin vitro testing conditions did not significantly affect the flexibility of spinal specimens (Due to the specific nature of experimental testing of biological materials, the present study entails several limitations. While it was shown that the chosen pecimens , the ROMpecimens , which vpecimens , as wellpecimens . Howevern = 8 was used, which is generally sufficient for the calibration and validation of numerical models and the interpretation of in vitro data. Compared to the sample size of clinical studies and considering certain data variability in the testing of biological materials, however, the sample size of the present in vitro study is too low to allow direct clinical conclusions. Therefore, the presented data including the significant differences between the single resection steps should primarily be used for the calibration and validation process of numerical models of the thoracic spine, which then can be used for the evaluation of novel surgical treatments. Statistical comparisons and interpretations of differences between the intact condition and both monosegmental conditions were not performed in this study due to the fact that resections were performed in different anatomical planes, making definite conclusions difficult. Moreover, multiple testing would have potentially caused cumulated α errors, which could have led to reduced statistical power after post hoc correction, especially regarding the small differences in ROM on segmental level.In the present study, a sample size of in vitro studies using stepwise resection of single rib cage structures (Using the data presented in this study, numerical models can be calibrated more accurately by adapting their material properties to reproduce the experimentally determined ROM data. The data can be used either for polysegmental models with rib cage or monosegmental models with or without ribs in addition to data from previous ructures  and funcructures , as wellructures . In caseThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the Ethics Committee Board University of Ulm, Ulm, Germany; ethik-kommission@uni-ulm.de. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.CL: study design, experimental testing, data analysis, and manuscript preparation. H-JW: funding acquisition, planning, discussion, and manuscript review.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.


Once metal-based engineered nanoparticles (NPs) are released into the aquatic environment, they are expected to interact with other existing co-contaminants. A knowledge gap exists as to how the interaction of NPs with other co-contaminants occurs. Here we selected ZnO NPs among various NPs, with Ag ion existing as a contaminant in the aquatic environment by Ag NPs widely used. A novel modeling strategy was demonstrated enabling quantitative and predictive evaluation of the aqueous mixture nanotoxicity. Individual and binary mixture toxicity tests of ZnO NPs and silver (as AgNO3) on Daphnia magna were conducted and compared to determine whether the presence of Ag ions affects the toxicity of ZnO NPs. Binary mixture toxicity was evaluated based on the concentration addition (CA) and independent action models. The CA dose-ratio dependent model was found to be the model of best fit for describing the pattern of mixture toxicity. The MIX I and MIX III suspensions (higher ratios of ZnO NPs to AgNO3) showed a synergism, whereas the MIX II suspension (lower ratio of ZnO NPs to AgNO3) showed an antagonism. The synergistic mixture toxicity at higher ratios of ZnO NPs to AgNO3 was caused by either the physiological or metabolic disturbance induced by the excessive ionic Zn or increased transport and accumulation in D. magna via the formation of complex of ionic Ag with ZnO NPs. Therefore, the toxicity level contributed via their aggregation and physicochemical properties and the dissolved ions played a crucial role in the mixture toxicities of the NPs.  GivenDaphnia magna varied greatly with the concentration of NPs  in the mixture was determined using the effective concentration  of each chemical causing 50% immobilization to D. magna obtained from the individual toxicity test. The sum of TU  of each chemical in the mixture ranged from 0.06 TUmix to 2.0 TUmix, and each chemical in the mixture was adjusted to three different TU ratios . The observed mixture toxicity effects were compared with the predicted toxicity effects based on both the CA and IA reference models using the MIXTOX model of Jonker et al. /[CAgNO3] exceeded 2204. Therefore, the model of best fit was achieved with IA-DR , the representative light microscopy images of the organism exposed to a 0.5 TU level of each mixture suspension showed that a considerable number of NPs was taken up by D. magna  showed a synergism, while the MIX II suspension (high Ag ions) showed an antagonism. However, in the previous study, a synergistic effect was depicted when the concentrations of Ag ions increased in the mixture of Ag ions and Ag NPs, while antagonism was observed with Ag NPs increase in suspension [Together with the ICP-MS analysis data on the accumulated Zn and Ag ions in D. magna . In partto MIX I  than MIXto MIX I . This fispension .Figure 52+ and Mg2+, for the binding sites. Such competition would occur regardless of the mixture suspensions applied in the present study. However, even though this is true, it is expected that these competitions would differ between suspensions. Considering the lower TU ratio of ZnO NPs to AgNO3 in MIX II than those in the other mixture suspensions, the competition between ionic Zn and dissolved ionic Ag would be more likely to occur in MIX II compared to the other mixture suspensions. Thus, it is postulated that the increased competition between ionic Ag, Zn, and other cations may cause an antagonistic effect in this mixture suspension.In general, if the Zn ion is released from the ZnO NPs into the test media, it is expected that the Zn ion will interact or compete with not only ionic Ag but also other cations present in the medium, such as Ca3 might be due to either physiological or metabolic disturbance induced by the excessive Zn ion or the increased transport and accumulation in D. magna via formation of ionic Ag-ZnO NPs complexes , or  ZnO NPs ; however3 and ZnO NPs. When ZnO NPs are released into an environment where Ag already exists, it can interact to varying degrees depending on the ratio in the mixture, thus its effect on aquatic organisms can vary. Therefore, to facilitate the use of mixture toxicity studies in a prospective risk assessment, there is a need to improve understanding of how NPs will behave and interact with other co-contaminants existing in aquatic environments under environmentally realistic concentrations.In general, the CA model is more suitable as a reference model for environmental risk assessment  because D. magna.Since we have reported the mixture nanotoxicity at a whole organism-level in this work, the next step will be an in-depth mechanistic study on the cellular toxicity pathways at the molecular level, associated with tissue-specific toxicodynamics. Furthermore, the exact evaluation of uptake levels of Zn and Ag is required for the future research, under the consideration of time-dependent biodistribution profiles inside 4.The present study showed DR dependent deviation in both reference models. The lowest SS was obtained in the CA-DR model, suggesting that CA-DR would be the model of best fit to describe the pattern of mixture toxicity of ionic Ag and ZnO NPs. Specifically, antagonism occurred when Ag ions became dominant in the mixture, while synergism occurred when ZnO NPs became dominant in the mixture, showing a shift between synergism and antagonism that was dependent on the TU ratio of the mixture constituents. Given that the mixture toxicity cannot be predicted by the general conceptual CA model, further studies on the mixture toxicity of NPs and coexisting contaminants in environmentally realistic concentrations are required.Click here for additional data file.