In this manuscript, we review the management strategies available for high-grade serous ovarian cancer patients and the molecular advances that are helping improve our understanding of the tumor and its response to treatment. We emphasize the role that proteomics is now playing in the study of ovarian cancer tumors and how its integration with genomics can guide the development of new biomarkers and therapeutic targets.High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients. We provide a comprehensive review of HGSC, focusing on the most important molecular advances aimed at providing a better understanding of the disease and its response to treatment. We emphasize the role that proteomic technologies are now playing in these two aspects of the disease, through the identification of proteins and their post-translational modifications in ovarian cancer tumors. Finally, we highlight how the integration of proteomics with genomics, exemplified by the work performed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), can guide the development of new biomarkers and therapeutic targets. High-grade serous ovarian cancer (HGSC) is the most common and deadly subtype of ovarian cancer . It is cEpithelial ovarian cancer (EOC) is the 8th most common cancer in women and the 7th leading cause of cancer mortality in women worldwide . AlthougHGSC is thought to originate from precursor epithelial lesions in the fimbriated end of the fallopian tube although a proportion of HGSC presents without fallopian tubal involvement. It seems TP53 mutations may be an early event in the genesis of a proportion of HGSC occurring in p53 signature foci in the distal fallopian tube and the development of serious tubal intraepithelial lesions (STIC) . HGSC isTumor staging is based on the surgical assessment and pathological evaluation of cancer at the time of surgery following standardized criteria by the International Federation of Gynecology and Obstetrics (FIGO) . The comDespite effective treatment, ~75% of women with HGSC will develop recurrence and ultimately succumb to their disease . AlthougMonitoring of disease recurrence is usually performed by clinical examination, imaging techniques, and serum CA125 levels. However, the use of these examinations is widely variable amongst different gynecological oncology society guidelines. Increasing levels of CA125 are generally not sufficient to initiate treatment unless a patient is symptomatic or is enrolling in a clinical trial. In addition, some patients with recurrence may not present with increased levels of CA125. Alternative markers such as HE4 are also being evaluated for the monitoring of disease recurrence and progression . There aIn addition to the chemotherapy regimens used in the first and second-line setting, several targeted therapies are being investigated for the management of HGSC. Antiangiogenic therapy and PARP inhibitors are the only targeted therapies currently approved for the treatment of HGSC in the maintenance and recurrent setting. Inhibition of tumor angiogenesis with bevacizumab, an anti-vascular epithelial growth factor (anti-VEGF) monoclonal antibody, has proven to be effective for the treatment of advanced-stage HGSC. Several randomized-controlled trials have shown improved PFS rates when used in addition to standard chemotherapy and platinum-sensitive and platinum-resistant recurrent disease ,31,32,33PARP inhibitors are rapidly expanding and transforming the treatment of HGSC. These drugs target the PARP family of enzymes, principally PARP1, which play a major role in DNA repair. PARP inhibition leads to the accumulation of single-strand breaks (SSB) by disrupting the BER pathway and also causing PARP1 trapping by inhibiting auto-PARylation and/or PARP release from the DNA . These eFinally, multiple trials are now assessing the combination of PARP inhibitors with other targeted therapies such as bevacizumab . In addiIt is therefore clear that a better understanding of HGSC tumor mechanisms is still required beyond current genomic knowledge to open new therapeutic opportunities and improve patient management. To achieve this, the incorporation of proteomics into ovarian cancer research is playing a crucial role to determine distinct HGSC phenotypes associated with patient clinical outcomes and the stratification of patients for adequate diagnosis and prediction of treatment response.Large-scale sequencing aimed at elucidating the key genomic changes occurring in different types of cancer have allowed the generation of large comprehensive genomic data. The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have sequenced thousands of tumors across different cancer types allowing the identification of novel specific genomic profiles that are potentially clinically targetable . TCGA anAlthough genomic analyses have greatly improved our knowledge of HGSC, it is now clear that the molecular mechanisms of HGSC are not fully captured by genomic and transcriptomic analysis , thus reMass spectrometry (MS) is currently the technology of choice for large-scale proteomic analysis allowing proteins to be analyzed rapidly, accurately, and with high sensitivity . The recSeveral studies have analyzed protein changes in ovarian cancer cell lines for the investigation of signaling events, cellular perturbations, and response to therapies ,70,71. PBeyond proteome characterization, several studies have used proteomic approaches to specifically study protein PTM events in ovarian cancer tissues, including phosphorylation, glycosylation, and ubiquitination events, among others. The study of PTMs is essential to obtain functional information on the dynamic regulation of tumor signaling networks. Although it is now clear that HGSC is a separate subtype of EOC with unique molecular and clinical features, many studies to date have failed to make this distinction. When describing these studies we refer to EOC when, in addition to HGSC, other subtypes have been included in the analysis. Several studies have been performed by the CPTAC and other authors to provide a deeper understanding of HGSC tumors ,58,73,74Besides phosphorylation, TCGA tumor samples have also been employed to study other PTMs and their role in HGSC pathogenesis. Protein glycosylation has also been assessed in 119 samples to investigate its role in the heterogeneity of HGSC . The autFinally, efforts are being made to integrate the information provided by different PTMs and their complex interplay in HGSC tissues to provide an additional level of information to the tumor signaling networks. Our group has recently performed a multi-layered analysis evaluating proteome, phosphoproteome, and ubiquitinome changes in patient-derived HGSC tumors according to their BRCA1 mutation status. Our results evidence a tight coordination between ubiquitination and phosphorylation regulatory layers and their role in major cellular processes related to BRCA1-dependent HGSC pathogenesis, including DNA repair, RNA splicing, transcription regulation, and PI3K/AKT/mTOR signaling.In addition to understanding HGSC tumor mechanisms through the study of proteins and their PTMs, the study of proteins can also help us classify patients according to a specific response to treatment or their disease prognosis. The introduction of biomarkers for cancer therapy has allowed the traditional clinical practice to move towards a more stratified approach by adding a biomarker-associated step to assign a patient to a specific management strategy or therapy. Despite the promising advantages of moving towards a stratified medicine in ovarian cancer, there are currently no approved biomarkers available for the prediction of treatment response and disease prognosis .Because proteins are the biological endpoints that control the majority of biological processes in the cell and are the targets of most current drugs, great efforts are being made to find protein cancer biomarkers of clinical utility. To date, the biomarker studies available from patient samples mainly come from genomic data. However, to date, these have limited clinical applicability beyond the identification of BRCA mutations and HRD status. Numerous studies have reported that mutations in the BRCA1 and BRCA2 genes are associated with increased response rates to platinum-based chemotherapy and better survival outcomes, especially for BRCA2 mutations ,52,79. IA variety of proteins have been identified to predict response to treatment in ovarian cancer both from in vitro and in vivo studies ,86. For Studies evaluating predictive protein markers in ovarian cancer tissues using proteomic approaches are scarce. A recent study compared the proteomes of platinum-sensitive and platinum-resistant HGSC using FFPE tissues from omental metastasis. CT45 was found to be overexpressed in chemosensitive tumors and associated with longer survival . CT45 waFinally, with the introduction of targeted therapies for the treatment of ovarian cancer, efforts are also been made to identify predictors of response to these therapies, although these are proving challenging. Angiogenic markers such as CD31 expression, microvessel density, and tumor VEGF-A levels were identified in a retrospective analysis of the GOG 218 study as potential predictive and prognostic biomarkers of response to anti-angiogenic therapy . A discrOvarian cancer represents a heterogeneous disease with unique histological subtypes that differ in their clinical presentation, genomic profiles, response to treatment, and prognosis. HGSC is the most common and deadly subtype and the focus of most comprehensive ovarian cancer studies. Recent molecular advances have provided useful insights into HGSC tumor biology. However, these findings have not been sufficient to understand its clinical behavior and translate into improved clinical outcomes.Proteomics provides an additional functional layer of information able to enhance our knowledge of the complex physiology of HGSC tumors, firstly, through the understanding of the tumor mechanisms and the identification of actionable therapeutic targets and, secondly, through the identification of protein biomarkers able to predict treatment response and disease prognosis. Mass spectrometric (MS) approaches enable a systematic interrogation and characterization of proteomes from complex samples with high sensitivity, precision, and sample throughput. However, the implementation of meaningful results obtained by MS technologies is currently limited by their transferability to other techniques of routine use in the clinics .MS-based proteomics technology must move beyond its current role as a powerful research tool in specialized laboratory environments to clinical settings, in the same way as MS has been adopted in the fields of clinical microbiology and the characterization of small molecules . There is no doubt that proteomics will continue to provide a valuable resource to unravel the complexity of HGSC tumors and that its integration with other disciplines will be essential for improving patients’ outcomes and advance towards more personalized patient care.


International Journal of Molecular Sciences Special Issue on the Barrier Function of Skin and Oral Mucosa aware of the content of the first edition on this same topic. Some highlights are noted.This is an attempt to make readers of the second edition of The roles of lipids in the barrier function of skin and advanced methods for permeability enhancement for the purpose of transdermal drug delivery were reviewed . The perSeveral studies demonstrated the dependence of skin barrier function on various physical aspects of the stratum corneum (SC) lipids. One study demonstrated that the repeat distance of the long lamellar phase depends upon the chain length of the free fatty acids . NormallSeveral manuscripts examined methods to overcome the skin barrier for the purpose of drug delivery. One of these reviewed the literature on lipid-based nanosystems . This inCandida albicans infection. Laser treatment can also promote skin wound healing. The ruby laser is used for removal of birth marks and tattoos.One review discussed the effects of different wavelengths of light on skin . DeleterAir pollution, including fine particulate material, is damaging to the skin barrier. A multimodal nonlinear optical imaging system has been described to visualize the deposition and penetration of particulate matter into human skin .The skin barrier function is impaired in a variety of inflammatory skin diseases including atopic dermatitis and psoriasis. Strategies for developing optimal formulations for topical therapy of such conditions have been presented . The impA major causative factor in skin cancer is UV radiation. Other life-style factors that influence skin carcinogenesis include age, smoking, alcohol consumption, dietary fiber, obesity and circadian rhythm disruption . CircadiSeveral articles dealt with skin problems relating to aging. 11β-hydroxysteroid dehydrogenase type 1 was shown to be at higher levels in human stratum corneum and oral epithelium compared to younger subjects . The resIn one study, barrier function of cultured human skin equivalents was optimized by adjusting three factors . It had In another study, human oral mucosal stem cells were isolated and grown in supplemented hormone epithelial medium . The celAutophagy plays an important role in epidermal homeostasis . This in


This review describes different trials to model and predict drug payload in lipid and polymeric nanocarriers. It traces the evolution of the field from the earliest attempts when numerous solubility and Flory-Huggins models were applied, to the emergence of molecular dynamic simulations and docking studies, until the exciting practically successful era of artificial intelligence and machine learning. Going through matching and poorly matching studies with the wet lab-dry lab results, many key aspects were reviewed and addressed in the form of sequential examples that highlighted both cases. Nowadays, many efforts are exerted in the pharmaceutical field regarding the development of different types of drug delivery systems (DDS). This aims to keep the therapeutic efficacy of the active pharmaceutical ingredient (API), and successfully deliver the proper dose to the physiological target site. Among different types of existing DDS, nanocarriers have gained great interest due to their ultra-small size that controls the pharmacokinetics and pharmacodynamics of the drug ,2. NanocAlong with the review, the reader can find brief definitions and explanations of the mentioned tools. Furthermore, some hints are provided that may help future tuning of technique selection. H) as follows:The essence of DL optimization is to predict molecules’ preferences in excipients depending on their physicochemical properties ,11. Thesn kelvin .1/2 was commonly considered as the best approximation that represents all the studied cases. Because of the extensive investigation of this old model, examples are limited to the most recent applications and do not cover all similar cases  constitutes the driving force of the model. In other words, components with nearly the same solubility parameters are potential companions and vice versa. Actually, the threshold of Δδ below which components are considered soluble slightly differs among published papers. For uniformity, a difference of fewer than 4 MPaar cases .H to predict several drugs payload in different nano-formulations using different carriers. In Ghitman et al. work . Ho. Ho53]. Dhanasekaran et al.  further Between success and failure stories of simulations and docking, the key strength and weaknesses at the same time of these techniques lie in their versatility. In docking, this can be best understood from the multiple engines available for conformations sampling  and poses ranking (scoring functions) ,56,57,58Artificial intelligence (AI) is another field of problem solving used for complex multivariable data. The term originates from the fact it is a kind of simulation of human brain intelligence in machines that are programmed to think and act like humans. One great advance in this field is machine learning (ML), both supervised and unsupervised. Focusing on the first type, supervised ML is an area in AI which has the ability to learn and model the relationship between a set of independent variables and an outcome (response) . The netHathout and Metwally experienced this concept in their previous work ,46. The 2 of >0.9  and determination coefficient of the regression line forced to come through the origin (R20) tested the predictive power of the model and retained a good fit between the predicted and observed target properties (Combining computed descriptors with experimental conditions, Cern et al.  developeoperties .Overall, these results are encouraging regarding payload prediction. Also, configuring the most important descriptors may be a mirror image to the possible interaction mechanism responsible for affinity during MD simulations and docking calculations ,72,73,74In this review, an overview of the evolution of in silico formulation design technology in the investigation and prediction of drug payload in lipid and polymeric nanocarriers was presented. As illustrated, this technology is close to becoming routine add-ins for formulation scientists even for non-informatics specialists. They represent the next industrial revolution and deserve many other reviews to describe. Going from simple thermodynamic models to the 3D MD-docking approaches and AI-oriented algorithms, the extent to which a specific technique can guide the process of drug loading and formulation development have been explored. The researcher applying the idea has the welling to choose the most favorite/suitable technique from the above discussed ones or even merge between them.


The historical hypothesis of sterility of the lungs was invalidated over a decade ago when studies demonstrated the existence of sparse but very diverse bacterial populations in the normal lung and the association between pulmonary dysbiosis and chronic respiratory diseases. Under mechanical ventilation, dysbiosis occurs rapidly with a gradual decline in diversity over time and the progressive predominance of a bacterial pathogen (mainly Proteobacteria) when lung infection occurs. During acute respiratory distress syndrome, an enrichment in bacteria of intestinal origin, mainly Enterobacteriaceae, is observed. However, the role of this dysbiosis in the pathogenesis of ventilator-associated pneumonia and acute respiratory distress syndrome is not yet fully understood. The lack of exploration of other microbial populations, viruses (eukaryotes and prokaryotes) and fungi is a key issue. Further analysis of the interaction between these microbial kingdoms and a better understanding of the host−microbiome interaction are necessary to fully elucidate the role of the microbiome in the pathogenicity of acute diseases. The validation of a consensual and robust methodology in order to make the comparison of the different studies relevant is also required. Filling these different gaps should help develop preventive and therapeutic strategies for both acute respiratory distress syndrome and ventilator-associated pneumonia. The lung microbiome has been studied for a decade. The key result of the earlier studies was to contradict the hypothesis of sterility of the lung, a notion long taught to medical students ,2. LaterThe microbiome is a diverse ecosystem that includes all host-associated microorganisms and their genomes . These mP. aeruginosa  (p = 0.049). Interestingly, airway colonization with C. albicans in a murine model induced a Th1-Th17 immune response that promoted the development of bacterial pneumonia through the inhibition of bacterial phagocytosis by alveolar macrophages  p = 0.0. InteresAscomycota and Basidiomycota) in 31 patients with pneumonia and 6 controls [Candida within this mycobiota [Candida representing 75% of the identified species. An antibiotic therapy had no noticeable effect. More recently, Fang et al. studied the diagnostic performance of shotgun sequencing in VAP and found Candida albicans, Aspergillus and Candida tropicalis to be the three most commonly identified genera or species  [To date, only three studies have looked specifically at the mycobiota of ventilated patients with pneumonia. Bousbia et al. identified 22 fungal species belonging to two phyla  . ConventMost studies of the lung microbiome have until recently been limited to the sole bacterial microbiota, using 16S rDNA genes  sequencing. No study has really focused on the evolution of the mycobiota or the virome in ventilated patients, whereas fungal lung colonization and viral reactivation are extensively described in this particular population ,52. DefiSuch studies will help to uncover how fungi contribute to the healthy equilibrium in the respiratory tract and how lung dysbiosis evolves during Candida spp. bronchial colonization to eventually favor emergence of VAP. In the same way, exploring how reactivation of eukaryotic viruses plays a role in lung dysbiosis and host response would provide a greater understanding of VAP and ARDS pathophysiology and prognosis. In addition, bacteriophages, viruses of the bacteria, represent probably most of the viral population within the human respiratory tract. It therefore appears essential to study simultaneously the bacterial microbiota, the mycobiota and the virome to obtain a comprehensive view of the lung dysbiosis associated with mechanical ventilation, VAP and ARDS . SettingThis approach would need serious technical development. The validation of a unique nucleic acid extraction protocol for bacterial, fungal and viral nucleic acid would enable an investigation of the entire microbiome profile and its evolution in ventilated ICU patients for large cohort studies.Another issue is the absence of reproducibility of clinical studies exploring the lung microbiome, a fact possibly linked to methodological issues. For instance, major differences exist in protocols applied to sequence the 16s rDNA from one study to another . These differences limit the comparison of published data . TechnicBacteroidetes and Firmicutes being predominant in the normal lung microbiota [Bacteroidetes and Firmicutes, which are notably composed of non-pathogenic anaerobes [Proteobacteria [The concept of lung sterility and of a sole bacterial species responsible for pneumonia has been largely refuted by the emergence of high-throughput sequencing projects. This simple, original conceptual framework has been replaced by a much more complex model in which the lung is inhabited by very diverse microbial populations, crobiota . Disequicrobiota ,9 and innaerobes ,15,16. Tbacteria . This enbacteria ,13.Gammaproteobacteria including Enterobacteriaceae (Bousbia). In the study of Emonet et al., the relative abundance of Proteobacteria increased from 25% to 55% between the intubation time and the third day of mechanical ventilation in patients who eventually developed a VAP, and the relative abundance of Firmicutes decreased from 40% to 30% in the lungs and the oropharynx [Whether pulmonary dysbiosis is only a marker of a more general dysbiosis due to the severity of the critical illness or whether it plays a pathophysiological role in the occurrence of VAP or the prognosis of ARDS remains to be clarified . Bousbiaopharynx . Interesopharynx ,16.Rothia Lactobacillus and Streptococcus increases the risk of pneumonia [Prevotella melaninogenica in the nasal microbiome reduced the risk of influenza pneumonia due to an increased influenzae-specific IgA antibodies [The hypothesis of a specific pattern of lung dysbiosis during VAP or ARDS must be confirmed, and the direct role of this dysbiosis in the pathophysiology of these conditions remains to be clarified. Recent data suggest that the initial composition of the upper and the lower airway microbiota could have direct effects on an individual’s risk of lung infection. For instance, the predominance in the upper respiratory tract of neumonia . In conttibodies .Further longitudinal metagenomic studies are now needed to fully characterize pulmonary dysbiosis in ventilated patients who have developed a VAP or an ARDS to understand whether pulmonary dysbiosis is a cause, a consequence or both. These studies will have to use standardized methods that will allow their comparability.One of the daily issues intensivists face is the accurate diagnosis of VAP in ventilated patient. Regardless of the type of respiratory specimen, pathogen identification by conventional culture-based microbiology techniques is time-consuming and requires a minimum delay of 24–48 h. However, reducing the diagnostic delay is crucial to limit the overuse and misuse of broad-spectrum antibiotic therapy while avoiding excess mortality in case of inappropriate antibiotic therapy. In addition, ruling out a VAP will help to reduce antibiotic consumption and thus decrease antibiotic resistance in the hospital setting. In this context, “culture-independent” techniques based on molecular biology such as multiplex PCR are emerging, allowing the detection of pathogens and resistance markers in a delay reduced to few hours . HoweverMetagenomic next-generation sequencing (mNGS) provides a less biased approach which allows universal pathogen detection from clinical specimens and can be viewed as an ideal method to detect simultaneously bacteria, virus and fungi . RecentlChlamydia, Nocardia, Human adenovirus or Aspergillosis pneumonia based on mNGS result [However, a large application among ventilated patients has not been really performed until recently. Yang et al. had recently completed a proof-of-concept case-control study in ventilated patients. Among nine cases of CAP, five were positive with conventional culture. In the latter, nanopore revealed communities with high abundance of the bacterial species isolated by cultures. In culture-negative cases, a probable bacterial pathogen was identified in only one case . Li et aS result .Only one recent study by Fang et al. has tried to assess the diagnostic performance of mNGS using BAL in 72 patients with clinically suspected VAP, compared to conventional culture . For bac→ platform [→ MinION device  [Of note, these promising results were performed with next-generation specific platform BIGISEQplatform , or Oxfoies, UK) , techniqIn parallel to the challenges of VAP diagnosis, VAP prevention is of high importance for the management of ICU patients. Obviously, a better understanding of pathophysiological infectious steps can help to define targeted interventions on the bacterial microbiota, the mycobiota and the virome.Among them, we clearly need to know more on the complex interplay between these actors and the host environment and host response in order to better act upon emerging dysbiosis. Depending on the local immune balance between pro- and anti-inflammatory status, one can imagine that boosting immune response may be preferable to antibiotics that may further aggravate the dysbiosis at some moments and that at others, preventive antibiotics may be a preferable option. To that effect, the effect of aerosolized amikacin on the lung microbiota composition could be an interesting lead. It will be evaluated in an ancillary study of a randomized controlled study assessing the preventive effect of aerosolized amikacin in patients at high risk of VAP . In thisTargeting very specific bacterial strains with bacteriophages may also be an interesting field to treat lung dysbiosis and restore normal flora. The same reasoning may be held with antiviral treatment of viral colonization or co-infection.To obtain a comprehensive view of the lung microbiome, including not only bacterial but also viral and fungal data, is of great value to improve our understanding of critical lung illnesses such as VAP or ARDS. The evolution of the lung microbiome over time and the description of its dysbiosis will be key elements to improve diagnosis and preventive measures in ventilated patients.


Data regarding the inter- and intraobserver variability in the radiological assessment of sialolithiasis using cone beam computed tomography are missing in the current literature. This study assessed the inter- and intraobserver variability in the radiological assessment of sialolithiasis using cone beam computed tomography (CBCT). In 107 patients, 130 salivary glands (65 parotid and 65 submandibular) with clinical signs of obstruction were assessed by four independent observers; 2 residents OMFS and 2 experienced OMFS. The observers analyzed the CBCT images and determined the absence or presence of one or more salivary stones in the affected gland. This procedure was repeated after three months. Interobserver agreements showed kappa values of 0.84 for the parotid gland, and 0.93 for the submandibular gland. Intraobserver agreements for the whole group reported kappa values between 0.83 - 0.95. There was no significant difference between residents and experienced OMFS. Due to the good inter- and intraobserver agreement, CBCT appears to be a reproducible imaging modality for detecting salivary stones in patients with signs and symptoms of obstructed parotid and submandibular glands. Key words:Salivary gland calculi, cone-beam computed tomography, observer variation. Symptomatic sialolithiasis is a disease whereby the outflow of saliva of a major salivary gland is mechanically blocked due to calculi within the salivary duct. A salivary stone originates from a nidus that is composed of various ratios of organic and inorganic substances and can eventually lead to obstruction of a salivary gland duct. Patients often present with recurrent, sometimes mealtime-related, painful unilateral gland swelling. This can remain transitory or be complicated by a bacterial superinfection.et al reported that parotid glands are affected up to 40% of the cases which is very high percentage and may be explained by the sensitivity of the detection methods used  radiography, ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT) and sialography. Each of these imaging modalities has its own advantages and disadvantages. US and 2D radiography are routinely used owing to the readily availability cost-effectiveness, and absence and lower radiation dose, respectively .Recently more research attention is being paid to the conebeam computed tomography (CBCT) application for salivary stone diagnosis. A mean sensitivity and specificity for salivary calculus diagnosis of 98,85% was reported in a retrospective study . It was A prospective study to evaluate the value of CBCT in de detection of salivary stones prior to sialendoscopy, was performed by our research group . A sensiHowever, data regarding the inter- and intraobserver variability on the interpretation of CBCT images related to the possible presence of salivary stones are missing. But imaging techniques do not make diagnoses; rather, they aid observers who make the diagnosis -10. ObseThe patients were referred to the Department of Oral and Maxillofacial Surgery of the Medical Centre Leeuwarden, the Netherlands, for the diagnosis and management of salivary gland obstruction of the submandibular or parotid gland during the period January 2012 to August 2016. A CBCT scan was performed at the first visit to determine the absence or presence of one or more salivary stones. The selection of this cohort was described in our prospective study , 28 patiAll CBCT images were acquired with a PaX-Zenith 3D scanner  . The CBCT images were retrospectively analyzed using a workstation, which was technically approved for radiological diagnostics, consisting of a 17-inch LCD monitor and a computer. Four observers participated in this study: two experienced oral and maxillofacial (OMF) surgeons with each more than twenty years of clinical experience and two residents of OMF surgery with each a minimum of 2 years clinical experience. All the observers interpret daily CBCT images. The observers had freedom to navigate the CBCT images and they could adjust the greyscale.In the first session the observers were provided with the set of CBCT images and the specification of the affected gland . No further clinical information or patient data were given to the observer. The reviewing observers were fully aware that their judgment would be compared to others and had no calibration exercises beforehand. The observers analyzed the CBCT images and determined the absence or presence of one or more salivary stones in the affected gland . Three months after the first session, each of the four observers repeated the procedure. The order of data of the set was randomly changed.- Statistical analysisThe collected data were analyzed using statistical software SPSS (IBM SPSS Statistics 26) and R (version 3.6.3 (r77832)). R was used for assessment of the interobserver variability of all observers by calculation of Lights Kappa and kappa statistics of SPSS was used for assessment of the intraobserver variability by calculation of Cohens Kappa . Kappa . The folInter- and intraobserver variability rates are summarized in The results of the present study demonstrate good agreement in the radiological assessment of the absence or presence of salivary stones in the parotid and submandibular gland Fig. , Fig. 2 The result may be explained by the routinely daily exposure and therefore experience with interpretation of medical CT and CBCT images for various reasons by residents.In this study, cases with inter- or intraobserver disagreement showed specific diagnostic difficulties. Firstly, some cases were difficult to interpret due to anatomic interpretations, especially in the area on the medial site of the ascending ramus of the mandible where it may be hard to distinguish between stones in the deep lobe of the parotid gland, the uncinate processs of the submandibular gland, or the tonsil Fig. . SecondlA limitation of the current study is the exclusion of 28 patients from the original cohort due to missing data. Another limitation is that the data do not indicate whether the observers agreed in their assessment on the same calcification. In other words, observations with a true positive and false positive outcome could be scored as agreement.Other studies that have determined the inter- and intraobserver variability in the diagnostic assessment of various aspects on CBCT showed comparable good results, including buccal bone measurements of dental implants, assessment of temporomandibular joint condylar morphology, detection of periodontal defects, identification of apical periodontitis, assessment of impacted mandibular third molars, and mandibular condyle fractures -18. ThesBesides CBCT, a variety of imaging modalities is used for the detection of salivary stones. Each of these modalities has its advantages and disadvantages such as the sensitivity and specificity for the diagnosis of a salivary stone, dose of ionizing radiation, the costs and the readily availability of the technique in daily practice.US is the least invasive method. Based on low costs, high availability, and no radiation dosages, US is routinely used in many practices . The senDue to the low costs, high availability and low radiation dosages, 2D radiography is often used in daily practice but the sensitivity is quite low with a reported rate of 60.7% . For intMedical CT displays a high accuracy in the detection of salivary stones, with a reported sensitivity rate of 98% when using sialendoscopy as a gold standard . In our When a stone is detected on a CBCT-scan in a patient with clinical signs and symptoms of salivary gland obstruction, the majority of cases require treatment. A variety of minimally invasive techniques is available for this purpose: sialendoscopy, transmucosal surgical approach, a combined approach and intra- or extracorporeal stone fragmentation.et al. presented a therapeutic decision tree for determining the best minimally invasive technique to treat submandibular and parotid calculi, according to the diameter of the calculi and their position in the ductal system (Foletti l system . They sul system . More reCBCT appears to be a reliable imaging modality for detecting salivary stones in patients with signs and symptoms of obstructed parotid and submandibular glands with a good intra- and interobserver agreement.


Medical and surgical treatments aimed at curing severe liver diseases and prolonging the survival of patients have improved dramatically in recent years. These advances have mainly been achieved by obtaining a better understanding of the pathophysiology of liver diseases . New andJournal of Clinical Medicine (JCM) has been dedicated to collecting high-quality scientific contributions from leading experts by focusing on updating the horizon of new pharmacological therapies and new surgical approaches that can be applied to cure several types of liver diseases as a method to address this challenging topic in greater detail.A Special Issue in the Two studies investigated the current and future management of cholestatic liver diseases ,5. The fJCM [The current therapeutic strategies for the management of patients with cirrhosis are focused on the prevention or treatment of specific clinical complications such as ascites, gastrointestinal bleeding and hepatic encephalopathy . “EtioloJCM . Poorly JCM seems to show that the addition of tolvaptan prolongs the survival of patients with cirrhotic ascites compared to standard diuretic drug combination alone, especially when tolvaptan is started before high-dose furosemide administration [The development of ascites is one of the typical complications of advanced cirrhosis. Treatment of non-tense ascites comprises the assumption of a combination of furosemide and anti-aldosterone diuretics, accompanied by a restrictive sodium and water diet . Tolvaptstration . AlthougJCM, including the more recent data regarding the placement of a transjugular intrahepatic portosystemic shunt (TIPS) and chronic albumin administration [More challenging is the treatment of ascites when it reaches the stage of refractoriness. An updated and exhaustive analysis of this topic has been reported in this issue of stration . TIPS restration  and MATCstration  randomizJCM are devoted to exploring these clinical complications of cirrhosis. The most recent advances in the management of esophageal variceal hemorrhage in cirrhotic patients have been updated [In addition to ascites, gastrointestinal bleeding and the development of hepatic encephalopathy (HE) represent the other key determinants of the transition from clinically compensated to decompensated liver cirrhosis. Two contributions to the present issue of  updated . These g updated , only a HE in cirrhosis has profound implications in terms of the patients’ ability to fulfil their family and social roles, to drive and to provide for themselves. The past few years have been characterized by significantly more attention to HE and its implications. Its definition has been refined, and a small number of new drugs or alternative management strategies have become available, while others are underway . CurrentJCM [If the development of ascites, gastrointestinal bleeding, HE or any combination of these conditions are the distinct features of acute decompensation of liver cirrhosis, acute-on-chronic liver failure (ACLF) is a distinct syndrome that develops in patients with acutely decompensated chronic liver disease and is characterized by a high 28-day mortality rate. Thus, a special article dedicated to ACLF has been presented in this issue of JCM . The keyJCM [Due to the availability of direct antiviral agents (DAAs) for curing hepatitis C virus infection , the onlJCM . The maiJCM have been devoted to providing the main updated knowledge regarding the approach to treat patients with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). One article focused on CCA [Three contributions presented in this issue of d on CCA , and twod on CCA ,21. CCA Compared to patients with CCA, very different treatment scenarios are on the horizon for patients with HCC. In addition to the well-known therapeutic options referring to surgical resection or to locoregional treatments of the tumor, a very large quantity of data is expected from new systemic treatments based on the use of ICIs in combination with other agents, among which vascular endothelial growth factor (VEGFR)-targeted therapies generated very encouraging results. Therefore, atezolizumab  plus bevacizumab  has been approved as the first-line treatment option for advanced HCC, becoming the standard of care for these patients. Immunotherapy-based treatments will increase the landscape of HCC therapy soon. A very attractive first-line treatment modality in patients with intermediate-stage HCC is to combine locoregional treatments with ICIs, since ablative and intraarterial techniques indirectly induce a peripheral immune response that may enhance the effect of ICIs. Both radiofrequency ablation and transarterial chemoembolization induce necrosis of tumor cells, promoting the release of tumor antigens and the activation of immune-mediated death of tumor cells, which in turn stimulates a peripheral systemic immune response that is potentially amplified by the administration of ICIs. In contrast, the survival benefit for patients’ candidates for second-line treatment options (regorafenib/cabozantinib or ramucirumab), although significant, is still modest. Thus, nivolumab with or without ipilimumab and pembrolizumab received FDA approval as second-line treatments. JCM Special Issue [In addition to locoregional and systemic treatments, liver transplantation (LT) remains the better treatment option for a subset of patients with HCC, since the surgical procedure removes both the tumor and the liver at the same time, which remains the potential source of new neoplastic clones. The Milan criteria (MC) were developed more than 25 years ago and are still considered the benchmark for LT in patients with HCC. However, the strict application of MC might exclude some patients who may receive a clinical benefit from LT. Several expanded criteria have been proposed. Some consider pretransplant morphological and biological variables of the tumor, others consider post-LT variables such as the histology of the tumor, and others combine pre- and post-LT variables. More recently, the HCC response to locoregional treatments before transplantation emerged as a surrogate marker of the biological aggressiveness of the tumor to be used as a better selection criterion for LT in patients beyond the MC at presentation. These issues have been comprehensively updated in this al Issue  to preseal Issue ,23.JCM, where pros and cons for every new potential indication for LT have been critically discussed. Importantly, all newer indications for LT increase the pressure in an already difficult context of organ shortage. Strategies are therefore needed to increase the pool of transplantable organs, aiming to ensure a better balance between new candidate patients and available resources (organs). Moreover, a very challenging issue will be to optimize the patient selection criteria to ensure a clear gain in life expectancy for those who undergo LT, avoiding the increase in waiting list mortality for those patients who continue to await LT. A multidisciplinary transplant team is needed soon to face and solve this very delicate problem. Furthermore, the new scenario of transplants makes it essential to review and standardize ethical considerations across countries to ensure the same treatment options for all patients.HCC represents approximately 50% of the indications for LT in Europe and the US. Constant indications for LT are decompensated liver cirrhosis due to cholestatic and autoimmune liver diseases, as well as chronic HBV infection. Decompensated cirrhosis due to chronic HCV infection is declining as an indication for LT, while alcohol- and non-alcoholic steato-hepatitis (NASH)-related liver diseases have increased progressively as indications for LT in recent years. In addition to the established indications for LT, clinical conditions historically considered exclusion criteria for LT, such as severe alcoholic hepatitis (AH), acute-on-chronic liver failure (ACLF), colorectal cancer metastases and cholangiocarcinoma, have been considered new indications for LT in recent years, producing promising survival advantages for patients. This topic has been highlighted in a very updated review  presenteJCM showed that the COVID-19 clinical outcome of the LT population was not per se worse than that of the general population, although careful management of immunosuppressive therapy may be needed. In this regard, complete therapy discontinuation is not encouraged, but caution is needed in the use of mycophenolate mofetil (MMF), favoring tacrolimus (TAC) use. Anti-SARS-CoV-2 mRNA vaccine immunogenicity appeared to be low in LT patients, despite a booster dose being strongly recommended by the main scientific societies. The newest SARS-CoV-2 variants, such as Omicron, may further reduce vaccine-induced immunogenicity, suggesting that the level of surveillance should remain very high in this population.The COVID-19 pandemic has completely disrupted the global landscape of health systems. The repercussions have been highlighted in all sectors and in that of liver diseases. Data regarding the effect of COVID-19 on LT recipients are still scarce and often contradictory. A recent systematic review  presenteJCM entitled “New therapies for liver diseases”. All of them should be considered the beginning of a new era in exploring the pathophysiology of liver diseases and the mechanisms inducing cancer transformation of the liver with the help of technology, artificial intelligence and human perspectives. These new insights will promote the development of new and more effective treatments for several liver diseases that will improve quality of life and patient survival. As the Guest Editor of this Special Issue of JCM, I would like to express special thanks to the authors for their remarkable contributions and the reviewers for their professional comments. Furthermore, I would like to thank the JCM team for their professional and exceptional support that enabled the project to be achieved.A large body of new insights are derived from the collective work presented in this Special Issue of


Prostate cancer is one of the most common malignant tumors that threaten the health of men. It is urgent to explore new molecular targets and develop new drugs for the treatment of prostate cancer. Circular RNAs (circRNAs) are aberrantly expressed in various malignant tumors. The dysregulated circRNAs are involved in the metastasis, tumor growth, drug resistance, and immunosuppression of malignant tumors. The present review systematically summarized publications concerning the biological implications of circRNAs in prostate cancer. The PubMed and Web of Science databases were used to retrieve publications concerning circRNAs and prostate cancer until June 16, 2021. The following keywords were used in the literature search: (circRNA OR circular RNA) AND prostate cancer. 73 publications were enrolled in the present systematic review to summarize the role of circRNAs in prostate cancer. The dysregulated and functional circRNAs were involved in the cell cycle, proliferation, migration, invasion, metastasis, drug resistance and radiosensitivity of prostate cancer. In addition, circRNAs could function through EVs and serve as prognostic and diagnostic biomarkers. Certain circRNAs were correlated with clinicopathological features of prostate cancer. A comprehensive review of the molecular mechanism of the tumorigenesis and progression of prostate cancer may contribute to the development of new therapies of prostate cancer in the future. Prostate cancer (PCa) is one of the most common malignant tumors that threaten the health of men. The American Cancer Society predicted 248,530 new cases and 69,410 deaths in 2021, ranked 1st and 2nd in men respectively  are covalently closed RNAs without 3′ or 5′ ends. High-throughput RNA-sequencing (RNA-seq) is the most commonly used method to identify new circRNAs by detecting the spliced reads that cover the back-splicing junctions. Once generated, circRNAs are highly stable due to their circular structure. Therefore, circRNAs in tissues, blood, or urine can be used as promising biomarkers  AND prostate cancer. The EndNote X9  software was used to manage the publications for the present review. In this article, meta-analysis was not performed. The present systematic review was based on previous publications so that ethical consent or approval was not required.Two reviewers (Fan Chao and Shiyu Wang) independently evaluated and selected the publications. Any discrepancy was resolved by the supervisor (Gang Chen). Publications that meet any of the following inclusion criteria were included: (i) expression of the circRNA was quantified in PCa; (ii) biological function and/or mechanism of the circRNA was determined; (iii) prognostic or diagnostic value of the circRNA in PCa was evaluated. Publications that meet any of the following exclusion criteria were excluded: (i) studies that did not meet any of the inclusion criteria; (ii) reviews, books, comments, patents, meeting abstracts and retracted articles; (iii) studies that were not related to circRNA or PCa.We retrieved 347 publications from the databases mentioned above and 229 publications after the removal of duplications. 156 publications were excluded after reviewing. Finally, 73 publications were enrolled in the present systematic review .Sry circRNA was discovered in the testis of adult mice and was considered to be the noise of normal splicing , exon-intron circRNAs (EIciRNAs), intronic circRNAs (ciRNAs), and tRNA intronic circRNAs (tricRNAs) . EcircRNCDR1as contains more than 70 sponging targets for miRNA miR-7. Although CDR1as is resistant to the miRNA-mediated degradation of target RNAs, it strongly inhibits the activity of miR-7 and thereby increases the level of other miR-7 targets  plays an important role in the metastasis of malignant tumors . Expression of the four most abundant circRNAs are upregulated during the castration-resistant progression of PDXs and can be detected in the plasma of patients with PCa. These AR-derived circRNAs might serve as biomarkers for CRPC. Greene et al.  hypothesis  vectors can be used in gene therapy of cancer due to its advantages including tissue specificity, long-term transgene expression, and low immunogenicity (Luo et al., Although a number of studies have reported the biological functions of circRNAs in prostate cancer, it is uncertain which ones are prostate-specific due to the lack of experimental verification. Further research should focus on discovering the prostate-specific circRNAs. Targeting prostate-specific circRNA and developing new therapeutic targets are of great significance.Researchers have reported the dysregulation of circRNAs and their biological function as well as the mechanism. Nevertheless, the reason why circRNAs were dysregulated was poorly studied. A previous study reported that the expression level of circRNA was positively correlated with its host gene (Chao et al., The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.FC performed the literature search, analyzed the data, made the schematic diagram, and wrote the manuscript. SW performed the literature search and the review on the overview of circRNA. CZ performed the review on the role of circRNA in PCa. DH determined the inclusion and exclusion criteria. GX revised the manuscript. GC conceived the idea and revised the manuscript. 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In the last decades, the effective management of some cardiovascular risk factors in the general population has led to a progressive decrease in the prevalence of coronary artery disease (CAD). Nevertheless, coronary heart disease remains the major cause of death in developed and developing countries and chronic coronary syndromes (CCS) are still a major target of utilization of non-invasive cardiac imaging and invasive procedures. Current guidelines recommend the use of non-invasive imaging in patients with CCS to identify subjects at higher risk to be referred for invasive coronary angiography and possible revascularization. These recommendations are challenged by two opposite lines of evidence. Recent trials have somewhat questioned the efficacy of coronary revascularization as compared with optimal medical therapy in CCS. As a consequence the role of imaging in these patients and in in patients with ischemic cardiomyopathy is under debate. On the other hand, real-life data indicate that a consistent proportion of patients undergo invasive procedure and are revascularized without any previous non-invasive imaging characterization. On top of this, the impact of COVID-19 pandemic on the sanitary systems caused a change in the current management of patients with CAD. In the present review we will discuss these conflicting data analyzing the evidence which has been recently accumulated as well as the gaps of knowledge which should still be filled. In the last decades, the prevalence of obstructive coronary artery disease (CAD) and significant myocardial ischemia has been progressively decreasing in stable patients –4. As a In patients with CCS, consistent evidence has challenged the concept that revascularization might improve prognosis more than optimal medical treatment (OMT) , 11. TheRecent publications have shown that the pre-test probability (PTP) figures in the previous “European Society of Cardiology” (ESC) guidelines were grossly overestimated . The curFirst, in most of these trials multiple, different and not necessarily equivalent modalities were used for the evaluation of myocardial ischemia , 6. SecoA final major limitation of these trials was that patient management was not guided by imaging results but left at the discretion of the referring physicians. Thus, the “appropriateness” of coronary revascularization, as defined by treating obstructive CAD associated with significant downstream ischemia and deferring revascularization in the other cases, could not be determined. In the ISCHEMIA study, ischemia was documented only by stress ECG in almost 25% of patients . MoreoveA final consideration applies to the prognostic efficacy of OMT when targeted to the coronary atherosclerotic and ischemic processes. The diffusion of computed tomography coronary angiography (CTCA) as a first screening test in patients with CCS has increased the recognition of coronary atherosclerosis even in its earlier non-obstructive stages. Including CTCA in the diagnostic process of patients with CCS has been shown to improve outcome as compared to standard of care , indepenIn conclusion, current evidence is in favor of an accurate assessment of coronary anatomic and ischemic burden in patients with CCS for risk-stratification and targeting of OMT . In patiThe choice of the best diagnostic strategy to be followed in specific categories of patients with CCS is still a matter of debate, given the presence of a limited number of comparative prospective studies in patients with suspected or known CCS. Despite classically considered interchangeable for diagnostic purposes, anatomical and functional imaging techniques allow the assessment of distinct aspects of CAD that are associated with specific risks and may possibly require individualized treatments. Current guidelines in CCS  recommenThe EVINCI-Outcome study, enrolling patients with stable angina submitted to both CTCA and stress imaging before ICA, provides evidence on the role of imaging to define appropriate treatment and the potential effects on prognosis in a contemporary population of patients with CCS and a low prevalence of disease (30%) . PatientLimited evidence exists on the possible additional role of combined anatomic/functional cardiac imaging in this setting. Nuclear stress imaging tests are well-suited to complement CTCA results also due to their recognized prognostic role , 33. IntCT , derived from the application of computational flow dynamics to standard CCTA datasets, had the main advantage to require a shorter computational time (20–30 min on average) to obtain the results in each case  is generally identified by the presence of significant left ventricular (LV) systolic dysfunction, as defined by LV ejection fraction (EF) lower than 40%, associated with the presence of extensive CAD . While sP = 0.006), this difference was obtained only after extensive follow-up, because the early increase in mortality related to cardiac surgery was offset by beneficial effects only after >4 years. The pre-specified viability sub-study of STICH included the 601 patients with available information on the presence and extent of myocardial viability, as obtained through single-photon emission computed tomography (SPECT) or stress echocardiography  trial is so far the largest RCT that has evaluated the impact of surgical coronary revascularization in patients with ICM. Of the 1,212 patients enrolled, 610 underwent coronary artery bypass graft (CABG) on top of OMT, while 602 patients were randomized to OMT alone . Despiteiography , 56. Whiiography . HoweverP = 0.16). However, at further analysis, patients with a more significant burden of hibernating myocardium (>7% of the LV) showed a prognostic benefit from coronary revascularization (event-rate 13 vs. 56% in non-revascularized patients) (The Positron Emission Tomography and Recovery Following Revascularisation (PARR-2) study randomized patients with ischemic heart failure to either a viability-guided management or standard care . Myocardatients) . Moreoveatients) .Available evidence does not allow to make a conclusive statement of the role of viability-guided management in patients with ICM, posing the need of dedicated RCTs on the topic.The management of patients with new onset or worsening symptoms suggestive of CAD has become a challenge for medical personnel and healthcare systems with the worldwide spread of the COVID-19 disease, starting from the end of 2019. As a rule, the normal function of the cardiac catheterization laboratories has been altered to minimize the risk of personnel infection, to preserve hospital beds and to prioritize procedures known to have a higher impact on patients' outcome . A natioAccording to available figures, the monthly PCI volumes from March 15 to April 15, 2020 as compared with the same period of 2019 was reduced by 55% and this reduction was mainly due to deferral of PCI for stable CAD. These data have been most probably also influenced by evidence accumulated from the recent RCTs on the management of patients with CCS, downplaying the role of invasive management. Interestingly, interventional cardiologists perceived that non-invasive imaging studies were 14–24% more likely to be used to risk stratify patients instead of angiography.P < 0.001] compared to 2019 (Interventional procedures with immediate mortality benefits, such as primary PCI in STEMI patients, remained prioritized in the hospital protocols . Neverth to 2019 . While a to 2019  (see the to 2019 .The reduction in coronary revascularizations was mirrored by the drop in the use of non-invasive diagnostic procedures in patients with suspected CAD during the COVID-19 pandemics. In a worldwide survey assessing alterations in cardiovascular diagnostic procedure volumes and safety practices resulting from COVID-19, non-invasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019 . OverallInternational scientific societies, such as the European Association of Cardiovascular imaging of the ESC, issued recommendation on cardiac imaging during the COVID-19 pandemic with special attention on indications and prioritization . The genDedicated studies will be warranted to assess whether some of the relevant changes in care delivery related with COVID-19 will last even after the pandemic period and whether these changes had an impact on cardiovascular outcomes.In the last decades, the role of coronary revascularization in patients with CCS has been progressively challenged. In this setting, non-invasive cardiac imaging, aiming at evaluating the presence of obstructive CAD and/or the extent of myocardial ischemic burden, is still recommended to identify individuals who might benefit more from an invasive management. Recent data have underlined the role of a sequential anatomical and functional diagnostic strategy to guide selective coronary revascularization and improve clinical outcome. This approach might be particularly suited in patients with ICM, in whom the risks of revascularization procedures are increased, and more targeted interventions are needed. Real-life data indicate, on the other hand, that a consistent proportion of patients undergo ICA and ultimately coronary revascularization without any previous characterization and proof of inducible myocardial ischemia, leading to inappropriate resources utilization and possibly a higher complications rate. During the COVID-19 pandemic the sanitary systems have been forced to reduce non-urgent interventional procedures including coronary revascularizations. While some useless procedures could have been avoided, there is clear evidence that unwanted delays have been accumulated in treating patients at high risk. This experience will probably further help to reconsider the effectiveness of current management of patients with CAD and prompt new trials to define the role of imaging guided revascularization vs. OMT.DN, NM-V, NC, and RL contributed to conception of the review. DN wrote the first draft of the manuscript. NM-V, NC, and RL wrote sections of the manuscript. RL assembled the final version. All authors contributed to manuscript revision, read, 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The reformations of the electrical power sector have resulted in very dynamic and competitive market that has changed many elements of the power industry. Excessive demand of energy, depleting the fossil fuel reserves of planet and releasing the toxic air pollutant, has been causing harm to earth habitats. In this new situation, insufficiency of energy supplies, rising power generating costs, high capital cost of renewable energy equipment, environmental concerns of wind power turbines, and ever-increasing demand for electrical energy need efficient economic dispatch. The objective function in practical economic dispatch (ED) problem is nonlinear and non-convex, with restricted equality and inequality constraints, and traditional optimization methods are incapable of resolving such non-convex problems. Over the recent decade, meta-heuristic optimization approaches have acquired enormous reputation for obtaining a solution strategy for such types of ED issues. In this paper, a novel soft computing optimization technique is proposed for solving the dynamic economic dispatch problem (DEDP) of complex non-convex machines with several constraints. Our premeditated framework employs the genetic algorithm (GA) as an initial optimizer and sequential quadratic programming (SQP) for the fine tuning of the pre-optimized run of GA. The simulation analysis of GA-SQP performs well by acquiring less computational cost and finite time of execution, while providing optimal generation of powers according to the targeted power demand and load, whereas subject to valve point loading effect (VPLE) and multiple fueling option (MFO) constraints. The adequacy of the presented strategy concerning accuracy, convergence as well as reliability is verified by employing it on ten benchmark case studies, including non-convex IEEE bus system at the same time also considering VPLE of thermal power plants. The potency of designed optimization seems more robust with fast convergence rate while evaluating the hard bounded DEDP. Our suggested hybrid method GA-SQP converges to achieve the best optimal solution in a confined environment in a limited number of simulations. The simulation results demonstrate applicability and adequacy of the given hybrid schemes over conventional methods. The essential purpose of the energy dispatch problem (EDP) is scheduling the electric generation of units to attain the lowest possible cost while also satisfying the constraints associated within the system. The optimal EDP solution is one of the most important factors in achieving the power system’s sustainability while focusing on low dispatch price, achieving demand-supply balance, and maintaining constraints such as valve-point loading (VPL) effects, prohibited operating zones (POZ), ramp-rate limits (RRL) and power generation limits –3. For tIt should be noted that machine-learning mechanisms are being utilized effectively in optimization and detection tasks, as observed in –16. SuchThe algorithm in  proposedThe performance of evolutionary algorithms for EDP is surveyed in the article . The enaFor the above listed literature research gap, a convex and non-convex cost model along with complex constraints in the form of single objective function is reformulated to attain an optimal solution of the cost and power.A GA-SQP approach is presented for DEPD through which the optimal selection of output powers of convex and non-convex machines reduce the total variable production cost thus improving the efficiency of plant and its life span.The approach considers several constraints, like VPL effects, POZ, RRL and power generation limits. To ensure the system security and to avoid system contingencies, the power demand of network is fulfilled efficiently by the proposed GA-SQP computing framework. The efficacy of presented methodology is tested for both type of machines by including all constraints.The selection of fuel type (MFO) with respect to its market price improves the unit cost of generating machines, which has been considered in the presented study compared to the existing studies.The optimal generation and less consumption of fuel also play role in environmental aspects and regulatory institutions of emission as a result protecting environment.The proposed GA-SQP approach has been compared with the existing studies of , 56–59. The primary concern of authors in this paper is to address the DEDP of non-convex machines for delivering a substitute solution by considering modern meta-heuristic techniques. The proposed approach considers GA as an initial search, followed by SQP for the fine tinning, by considering several system constraints. Comparing to the previous literature, our contribution is to deal with the complex problem based on soft computing framework while including several real-world constraints. The selection of machine is both convex and non-convex, and the designed algorithm provides confrontation for both systems. The outcomes of designed algorithm is faster convergence with finite time, best optimal conditions via handling hard bounded constraints, and less computational time and cost. The performance indexes of the designed approach addressed the generation cost considering practical constraints such as line losses, generation capacity, and valve-point loading effect, prohibited zones and multi-fueling option on standard IEEE bus systems. The major contributions in this work are outlined as follow:The rest of article consists of problem formulation of DEDP in Section 2. Section 3 provides the proposed GA-SQP framework of optimization and parameter settings for the listed problem. Simulation results, optimizer analysis, and machines details are listed in Section 4. Finally, Section 5 provides brief discussion and conclusions.The aim of DEDP is to allocate or assign optimal real generated powers to generators such that the cost involving in generation will be finest while satisfying the system associated constraints.n generating units on the basis of fuel cost is given as (see for instance ,Jij ∈ ℜ: Lb ≤ Jij ≤ Ub where Ub is upper bound and Lb is lower bound of both convex and non-convex machines.Step 2: This step involves the assignment of the general parameter setting of GA algorithm used in optimization framework as shown in Step 3: This step involves evaluating fitness function by acquiring the fitness of each agent in the form of mean square error as given below.jth committed units.Step 4: It is the termination criterion step, and algorithm is terminated on the following criterion.Fitness value is achieved as per definition.All defined generations are executed.Tolerance function value achieved.All optimization functions are evaluated.If all above conditions are achieved, stop otherwise run again.Step 5: The best generated solutions are provided as input to the final design of SQP for further refinement, random assignments with problem bounds according to parameter setting provided in Step 6: This step involves the assignment of optimist parameter known as toll initialization, and step size is also monitored in this step.Step 7: In this step the fitness function is evaluated according to the problem bounds with tuned tolerances setting.Step 8: If convergence is achieved and termination criterion is attained then final weights with execution time are saved, otherwise run again.In this section, MATLAB simulations for convex and non-convex objective functions for DEDP have been performed. All constraints such as transmission losses, power balance constraint, capacity constraint, and ramp limits were employed. The VPLE and MFO are also taken into account to demonstrate the efficacy of our designed soft computing framework. The parameter settings for the framework is shown in It is actually noticeable that for a hybrid framework that the level of accuracy is dominated as compared to separate local and global techniques. The computational budget for the hybrid approach can be significantly high as compared to the local search methodologies; however, this factor can be over-shed as the accuracy and constraint handling of hybrid schemes is more versatile as compared to the local ones. GA-SQP has a better likelihood of finding a global optimum than other algorithms. In practice, GA-SQP may reach a global optimum in a limited computational time in the nonlinear or multi-constrained situations that can be enhanced by hybridising with other methods. Another reason for the lower computational cost for the hybrid method can be the operational architecture of GA-SQP, which provides many options and allows the method to quickly converge on a single viable solution.The investigated problem may be divided into different groups, based on the nature of the fuel cost functions and constraints. In one category, DEDP problems with non-smooth cost functions as a result of taking VPL and MFO into account can be accounted. For such non-convex machines, the characteristics data of units has been provided in , 60, 69.We cannot relay on the value of local search methods because they often stuck on local minima due to poor initial guess. Another point to consider is that our designed framework provides consistency and stability with finer convergence rate with increase in number of machines and constraints of DEDP.This case study is composed of three non-convex machines with total load demand 850MW. The reference data along with fuel cost and VPLE coefficients are shown in The top fittest designed parameters that are actually the machine power generation values and are depicted in Now we consider the application of the proposed method over convex machines and consider three convex machines with total load demand 850MW , the maximum cost (Max cost), the mean cost (Mean cost), and the standard deviation of the cost (STD cost). Not only is the cost value analysed, but also the computational time required for optimization in terms of mean CPU time is also observed. The hundred independent iterations were performed for each case study and the optimal generated powers of committed units along with best computational budget and cost are tabulated in each case study via tables. The hundred independent iteration runs in simulations demonstrate that the output comes closer and closer to the optimal cost while maintaining the threshold criteria stated in There are some recent studies which have considered the convergence rate investigation by considering the rate of change of a factitious energy function –75 and . These mThis article discussed the key aspects and concerns of the DEDP problem. Two alternative formulations for the DEDP problem that are convex and non-convex cost functions were studied, and then a novel hybrid GA-SQP was presented to solve the DEDP. The presented scheme can be classified as an artificial intelligence technique, based on the hybrid GA-SQP approach. Due to the capacity of GA-SQP to seek the global optimal solution, the proposed method has been effectively utilized for solving DEDP with non-smooth or non-convex cost functions. It has been observed that hybrid approaches that integrate two or more optimization techniques are more successful in finding the global optimal solution for the DEDP with non-smooth or non-convex cost functions associated with nonlinear constrains. The aim behind the study is to solve the complex optimization problem with constraints for DEDP by considering MFO, RRL, and VPLE. The framework accomplished by coalesce heuristic ability of GA as a global search approach; and then results of that are refined through SQP. Ten highly nonlinear case studies with complex non-convex contiguous constraints were tested. The performance-based indices like computational cost, stability and handling of contiguous constraints validated the precision, dependability and unwavering quality of the proposed framework. While the sensible precision of framework is attained furthermore by acquiring optimal generations with satisfactory cost values. It is recommended to apply these tools to investigate multi-objective DEDP with environmental constraints. By comparing cost from existing papers mentioned in the case studies, our design scheme obtains optimal result while satisfying all constraints appropriately. In future, we can integrate conventional DEDP with environmental cost function along with the renewable energy resources to eliminate the dependency of fossil fuels.S1 Dataset(PDF)Click here for additional data file.


A variety of stimuli activating vestibular end organs, including sinusoidal galvanic vestibular stimulation, whole body rotation and tilt, and head flexion have been shown to evoke significant changes in blood pressure (BP) and heart rate (HR). While a role for the vertical semicircular canals in altering autonomic activity has been hypothesized, studies to-date attribute the evoked BP and HR responses to the otolith organs. The present study determined whether unilateral activation of the posterior (PC) or anterior (AC) semicircular canal is sufficient to elicit changes in BP and/or HR. The study employed frequency-modulated pulsed infrared radiation  directed via optical fibers to PC or AC of adult male Long-Evans rats. BP and HR changes were detected using a small-animal single pressure telemetry device implanted in the femoral artery. Eye movements evoked during IR of the vestibular endorgans were used to confirm the stimulation site. We found that sinusoidal IR delivered to either PC or AC elicited a rapid decrease in BP and HR followed by a stimulation frequency-matched modulation. The magnitude of the initial decrements in HR and BP did not correlate with the energy of the suprathreshold stimulus. This response pattern was consistent across multiple trials within an experimental session, replicable, and in most animals showed no evidence of habituation or an additive effect. Frequency modulated electrical current delivered to the PC and IR stimulation of the AC, caused decrements in HR and BP that resembled those evoked by IR of the PC. Frequency domain heart rate variability assessment revealed that, in most subjects, IR stimulation increased the low frequency (LF) component and decreased the high frequency (HF) component, resulting in an increase in the LF/HF ratio. This ratio estimates the relative contributions of sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) activities. An injection of atropine, a muscarinic cholinergic receptor antagonist, diminished the IR evoked changes in HR, while the non-selective beta blocker propranolol eliminated changes in both HR and BP. This study provides direct evidence that activation of a single vertical semicircular canal is sufficient to activate and modulate central pathways that control HR and BP. Prior studies have shown that vestibular inputs from otolith organs can modulate the autonomic pathway and contribute to the control of blood pressure and heart rate during movement. However, the role of the semicircular canals in this respect has not been completely clear. The present study elucidated the role for the vertical semicircular canals in altering autonomic activity using focused, pulsed infrared stimulation of posterior and anterior canals in the rat. Unilateral activation of either the posterior or anterior semicircular canal was sufficient to evoke profound changes in the heart rate and blood pressure, suggesting that canals also contribute to the vestibulo-autonomic pathway.The vestibular system is exquisitely sensitive to linear and angular accelerations of the head, informing the nervous system about head position and head movements in space. These two types of signals are detected by different sets of end organs, with the semicircular canals specialized to transduce angular accelerations and the otolith organs detecting linear forces such as gravity, tilt and translation. Vestibular information from both types of end organs is conveyed centrally to participate in well-characterized neural pathways involved in spatial orientation, gaze stabilization, balance, posture and cognition . FollowThe morphological basis for this vestibulo-autonomic activity has been demonstrated previously using sGVS to activate neurons in the caudal vestibular nuclei , and froWe used HRV analysis from the 17 rats (113 IR stimuli) receiving PC stimulation to further understand the effects of vertical canal stimulation on autonomic activity. HRV generally reflects the ability of the cardiovascular system to adapt to changing stimulus conditions and is used to assess fluctuations in autonomic innervation of the heart, as an alternative measure to average activity level. In general, healthy individuals have high HRV and reduced HRV is interpreted as an abnormal imbalance in the activity of the sympathetic and parasympathetic branches of the autonomic system . HoweverWe further investigated the tonic sympathetic and vagal influences on the heart with selective pharmacological blockade of cardiac autonomic receptors. The ACh antagonist atropine was used to inhibit the effects of excessive vagal activation on the heart. The non-selective beta blocker propranolol works by blocking epinephrine and norepinephrine at β -adrenergic receptors. The response after β-adrenergic receptor blockade with propranolol was used to estimate the sympathetic tone; the response after muscarinic cholinergic receptor blockade with atropine was used to assess the vagal tone . Our resThe present study demonstrates that activation of the vertical semicircular canals evokes significant autonomic activity in the anesthetized rats. The resulting decreases in MBP and HR confirm that these end organs provide a means for rapid detection and autonomic activation in response to a postural change. A direct comparison to the stimulation of unilateral otolith organs or augmentation of the responses seen here by otolith organs remain a goal for future studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Institutional Animal Care and Use Committee (IACUC) of the University of Miami.DR, GM, GH, and SR conceptualized, designed the experiments, and prepared the manuscript. DR, GM, WJ, and SR carried out the experiments and collected the data. DR, GH, and SR analyzed the data and prepared all the figures. All authors approved the final manuscript.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.


Which conditions treated by neurosurgeons cause the worst economic hardship in low middle-income in countries? How can public health financing be responsive to the inequities in the delivery of neurosurgical care? This review article frames the objectives of equity, quality, and efficiency in health financing to the goals of global neurosurgery. In order to glean provider perspectives on the affordability of neurosurgical care in low-resource settings, we did a survey of neurosurgeons from Indonesia and the Philippines and identified that the care of socioeconomically disadvantaged patients with malignant intracranial tumors were found to incur the highest out-of-pocket expenses. Additionally, the surveyed neurosurgeons also observed that treatment of traumatic brain injury may have to require greater financial subsidies. It is therefore imperative to frame health financing alongside the goals of equity, efficiency, and quality of neurosurgical care for the impoverished. Using principles and perspectives from managerial economics and public health, we conceptualize an implementation framework that addresses both the supply and demand sides of healthcare provision as applied to neurosurgery. For the supply side, strategic purchasing enables a systematic and contractual management of payment arrangements that provide performance-based economic incentives for providers. For the demand side, conditional cash transfers similarly leverages on financial incentives on the part of patients to reward certain health-seeking behaviors that significantly influence clinical outcomes. These health financing strategies are formulated in order to ultimately build neurosurgical capacity in LMICs, improve access to care for patients, and ensure financial risk protection. The costs accompanying the provision of neurosurgical care in low middle-income countries (LMICs) constitute as barriers to access among the socioeconomically disadvantaged . For theThe primary aim of the survey was to determine the most commonly encountered neurosurgical conditions that result in financial catastrophe. A secure online survey tool (Google Forms®) was used to disseminate the questionnaire to neurosurgeons currently practicing at public hospitals in Indonesia and the Philippines. Respondents comprised a purposive sample of neurosurgeons invited through the electronic mailing lists of neurosurgical training programs, email to personal contacts, and social media platforms (WhatsApp and Viber). The survey was open between 16th February 2021 and 16th March 2021. Those eligible to complete the survey were neurosurgeons—either as residents or as consultants—whose practice involves a publicly-funded neurosurgical center as part-time or full-time healthcare provider. Duplicates were removed via matching those of an identical name and hospital. Because no patient information was requested from the survey, approval by an institutional review board was not needed. It is of note that while the vantage point of patients would be most ideal to take, the survey has the limitation of inquiring only from the perspective of neurosurgeons as health service providers because of its cursory nature in bringing the more important discussion on solutions to the fore.Using principles and perspectives from public health, contractual management, and financial management, we proffer potential solutions that can address the gaps in health financing of neurosurgical services in Indonesia and the Philippines. When viewed in a public-health context, the problem of catastrophic and impoverishing expenditures becomes more manageable. Existing frameworks from these disciplines permit exploration of financial risks that burden the patients that can potentially be averted by the roles of various agents in the surgical and health systems. We propose a conceptual framework for implementation to inform future policymaking related to the financing of public neurosurgical services in Indonesia and the Philippines.A total of 43 neurosurgeons−29 (67%) from Indonesia and 14 (33%) from the Philippines—had valid responses to the survey. Majority of respondents (31.8%) cited malignant intracranial tumors as the neurosurgical condition that causes the worst economic hardship among patients and their families, followed by traumatic brain injury (27.3%), spinal trauma and spinal cord injury (15.9%), and aneurysmal subarachnoid hemorrhage (15.9%).In terms of out-of-pocket (OOP) expenses for these conditions, malignant intracranial tumors were reported to impose the highest OOP expenses (43.2%), followed by emergency vascular diseases (38.6%), traumatic brain injury (34.1%), and degenerative spine disorders (34.1%) .Among the neurosurgical conditions needing greater financial subsidy, traumatic brain injury (27.3%) needed the most, followed by malignant intracranial tumors (18.2%), aneurysmal subarachnoid hemorrhage (15.9%), and spinal trauma and spinal cord injury (13.6%) .Few studies have examined the association between patient-level socioeconomic factors and outcomes across various diseases that are treated by the specialty of neurosurgery—pediatric hydrocephalus –8, craniThere are various reasons for the still prevalent high out-of-pocket expenses in LMICs, particularly in Indonesia and the Philippines. From the demand side of the healthcare system, both medical and non-medical costs account for the financial catastrophe suffered by poor patients following surgery . SurgicaFrom the supply side of the health system—the healthcare providers—publicly-funded hospitals generally provide the needed wide range of emergency and elective neurosurgical care for poor patients. These hospitals are primarily financed from taxation and are appropriated a yearly budget from the national government through the Department or Ministry of Health, or from local or state-run universities. Many public hospitals do not have the bare minimum neurosurgical implements, surgical intensive care units, and even a computed tomography scanner. These complicate the usual treatment pathway for a neurosurgical patient—turning it into a cumbersome navigation around a generally disjointed referral network of hospitals , 5, 29. Broadly, health financing comprises the mechanisms by which money is mobilized to fund and pay for health-sector activities, and how it is used, raised, and paid out to achieve health-related outputs . FinanciSocioeconomically disadvantaged patients who seek healthcare services are often price-sensitive because their limited means do not allow them to have the capacity to economically withstand adverse life events such as having a neurosurgical illness requiring hospitalization. In countries that do not have a fully responsive health financing or social protection mechanism—which is more often the case in LMICs—poor households with a sick member would finance their health-related costs by way of out-of-pocket expenses , 2. The Social health insurance (SHI) at the national level acts as a payer for health care goods and services in a country. The Badan Penyelenggara Jaminan Sosial Kesehatan (BPJSK) is the single SHI agency in Indonesia while its counterpart is the Philippine Health Insurance Corporation (PHIC) in the Philippines , 34. TheIdeally, the role of the SHI is to ensure that adequate resources are mobilized to meet the service entitlements of insured patients—ideally the whole population—and thus achieve “universal health coverage.” While financial risk pooling is important for equity considerations and financial risk protection of the insured, an added function of strategic purchasing by the SHI can drive the quality and efficiency of healthcare provision , 32, 35.Consider for example—traumatic brain injury (TBI)—for which the current standard of neurosurgical management is entrenched in universally accepted clinical practice guidelines . PrehospConceptually, strategic purchasing allows buying of health services for certain groups of patients and uses financial levers and payment schemes that influence the behavior of providers including hospitals and neurosurgeons , 36, 40.A prospective payment scheme brought about by strategic purchasing can enable the pooling of paid out funds on the part of provider hospitals to accrue future savings . The incNeurosurgical patients, herein considered the demand side of healthcare provision, constitute an important stakeholder in terms of health financing. Despite the fact that surgery in public hospitals is completely subsidized by the BPJSK in Indonesia and the PHIC in the Philippines—at little to zero cost for indigent patients—there remain substantial financial barriers . FrequenThe results of our survey show that out-of-pocket expenses surrounding the management of those with malignant intracranial tumors are a prevalent form of health financing in Indonesia and the Philippines. For majority of patients with brain cancer in Indonesia and the Philippines, the standard Stupp protocol for the treatment of glioblastoma could bankrupt their families—often resulting in the patient never receiving or completing the disease-altering adjuvant chemotherapy and radiotherapy. Adjuvant chemotherapy for glioblastoma is carried out on an outpatient basis: consultations are done at the oncology clinic during the course of the patient's ongoing intake of oral drugs (temozolamide). However, SHIs are currently not fully responsive in the aspect of financing for adjuvant therapy and outpatient care. The responsibility of payment for the adjuvant treatments is frequently left to the social welfare division of the hospital or external charitable organizations . In the The case for subsidizing the full costs of treatment for patients with glioblastoma is justified by its cost-effectiveness  and the CCTs for patients with glioblastoma may be done to decrease the no-show rate in follow-up consultation schedules and improve the all too common problem of loss to follow-up. The direct provision of cash for indigent patients can be made contingent on their adherence to adjuvant treatment following neurosurgical operation for glioblastoma. In turn, the families' non-medical costs are also subsidized. Furthermore, CCTs also have positive externalities and can be expected to increase the propensity of the household members to have some degree of trust in the systems of healthcare provision and health financing. In this manner, financial barriers to neurosurgical services are actually lowered and a system is set in place to reward beneficial health-seeking behavior that impacts patient outcomes.Neurosurgical patients living in Indonesia and the Philippines who are socioeconomically disadvantaged to begin with have the added challenges of incurring out-of-pocket expenses and risking financial catastrophe whenever they navigate the health system for treatment. This situation calls for a more robust and responsive health financing for neurosurgical services. From an economic perspective, health financing for neurosurgery entails the proposition for addressing the demand (patient) or supply (provider) sides of healthcare provision. Strategic purchasing enables a systematic and contractual management of payment arrangements that provide performance-based economic incentives for providers that can in turn help achieve the goals of quality and efficiency of neurosurgical care provision. Conditional cash transfers similarly leverages on financial incentives on the part of patients to reward certain health-seeking behaviors that significantly influence clinical outcomes. These health financing strategies are formulated in order to ultimately build neurosurgical capacity in LMICs, improve access to care for patients, and ensure financial risk protection. It is hoped that this article provides a framework for implementation and affords a basic understanding of health financing that can inform policy and advocacy work among neurosurgeons globally.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.KF, MY, and MB initiated and conceptualized the article design. KF drafted the manuscript. KF and DW collected and interpreted the data. MY, MB, SM, IW, RR, KS, and JN critically examined and commented on the manuscript. All authors revised and approved the manuscript.The opinions expressed by the authors in the discussion of this article do not necessarily reflect the opinions of the institutions to which the authors belong.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.