J. Pers. Med., Volume 11, Issue 4 (April 2021) – 82 articles

Background: Oral health-related conditions are among the common conditions seen in adults in India. The usage of inappropriate measurement tools that are unvalidated may result in deceptive and imprecise findings that might lead to substandard plans for cessation programs and ineffectiveness. This study was conducted to validate a questionnaire that can assess the factor structure of knowledge, attitude, and behaviour towards oral health among adults in India by confirmatory factor analysis. Methods: Simple random sampling was conducted among adults in India. A total of 260 adults participated in this study. The knowledge, attitude, and behaviour (KAB) questionnaire on oral health was circulated among the adults who were willing to participate in the study after it was explained to them, and the questionnaires were retrieved once they completed. Software R version 3.6 was used to analyse the data of this study. Robust maximum likelihood was utilized for the assessment due to the violation of multivariate normality assumption. For attitude and behaviour domain, a three-factor model was used for measurement model validity and construct validity. Results: The confirmatory factor analysis of the three-factor model for the 26-item KAB questionnaire on oral health gave sufficient goodness-of-fit values and the measurement model exhibited ideal convergent and discriminant validity following model re-specification. The three-factor model was tested to obtain measurement model validity and construct validity for attitude and behaviour domains. The results of this study gave a statistically significant value (p < 0.001), with χ² (df) values of 39 (7) and 28 (11) for attitude and behaviour domains, respectively. Conclusions: The KAB oral health questionnaire used in this study has a valid measurement model and reliable constructs. It was found to be an ideal tool to measure the KAB towards oral health among adults in India. Full article

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma. Full article

Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a novel coronavirus discovered in 2019 that caused the coronavirus disease 2019 (COVID19). During the last year, over 70 million people were infected and more than 1.5 million people died. Despite the tremendous number of people infected, children were less affected and presented milder forms of the disease. A short time after the pandemic was declared, a new hyperinflammatory syndrome resembling Kawasaki disease (KD) was described in children with confirmed or suspected SARS-CoV-2 infection named multisystem inflammatory syndrome in children (MIS-C). The incidence of MIS-C is low and it has a polymorphous clinical presentation, making the diagnosis difficult. Although the incidence is reduced, there is a high risk of cardiovascular complications. In order to raise awareness, we present the cases of two pediatric patients diagnosed with MIS-C in our clinic. Full article

Backgrounds: Social cognition is defined as the mental operations underlying social behavior. Patients with schizophrenia elicit impairments of social cognition, which is linked to poor real-world functional outcomes. In a previous study, transcranial direct current stimulation (tDCS) improved emotional recognition, a domain of social cognition, in patients with schizophrenia. However, since social cognition was only minimally improved by tDCS when administered on frontal brain areas, investigations on the effect of tDCS on other cortical sites more directly related to social cognition are needed. Therefore, we present a study protocol to determine whether multi-session tDCS on superior temporal sulcus (STS) would improve social cognition deficits of schizophrenia. Methods: This is an open-label, single-arm trial, whose objective is to investigate the efficacy and safety of multi-session tDCS over the left STS to improve social cognition in patients with schizophrenia. The primary outcome measure will be the Social Cognition Screening Questionnaire. Neurocognition, functional capacity, and psychotic symptoms will also be evaluated by the Brief Assessment of Cognition in Schizophrenia, UCSD Performance-Based Skills Assessment-Brief, and Positive and Negative Syndrome Scale, respectively. Data will be collected at baseline, and 4 weeks after the end of intervention. If social cognition is improved in patients with schizophrenia by tDCS based on this protocol, we may plan randomized controlled trial. Full article

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was significantly higher than that of normal ovarian tissue. Kaplan–Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better. The CREB1 gene may play a role in the occurrence and development of ovarian cancer by regulating the process of protein. Based on differentially expressed genes, 20 small-molecule drugs that potentially target CREB1 with abnormal expression in OV were obtained from the CMap database. Among these compounds, we found that naloxone has the greatest therapeutic value for OV. The high expression of the CREB1 gene may be an indicator of poor prognosis in ovarian cancer patients. Targeting CREB1 may be a potential tool for the diagnosis and treatment of OV. Full article

A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals. Full article

Traditional healthcare paradigms rely on the disease-centered approach aiming at reducing human nature by discovering specific drivers and biomarkers that cause the advent and progression of diseases. This reductive approach is not always suitable to understand and manage complex conditions, such as multimorbidity and cancer. Multimorbidity requires considering heterogeneous data to tailor preventing and targeting interventions. Personalized Medicine represents an innovative approach to address the care needs of multimorbid patients considering relevant patient characteristics, such as lifestyle and individual preferences, in opposition to the more traditional “one-size-fits-all” strategy focused on interventions designed at the population level. Integration of omic (e.g., genomics) and non-strictly medical (e.g., lifestyle, the exposome) data is necessary to understand patients’ complexity. Artificial Intelligence can help integrate and manage heterogeneous data through advanced machine learning and bioinformatics algorithms to define the best treatment for each patient with multimorbidity and cancer. The experience of an Italian research hospital, leader in the field of oncology, may help to understand the multifaceted issue of managing multimorbidity and cancer in the framework of Personalized Medicine. Full article

Patients with epilepsy frequently experience autonomic dysfunction and impaired cerebral autoregulation. The present study investigates autonomic function and cerebral autoregulation in patients with epilepsy to determine whether these factors contribute to impaired autoregulation. A total of 81 patients with epilepsy and 45 healthy controls were evaluated, assessing their sudomotor, cardiovagal, and adrenergic functions using a battery of autonomic nervous system (ANS) function tests, including the deep breathing, Valsalva maneuver, head-up tilting, and Q-sweat tests. Cerebral autoregulation was measured by transcranial Doppler examination during the breath-holding test, the Valsalva maneuver, and the head-up tilting test. Autonomic functions were impaired during the interictal period in patients with epilepsy compared to healthy controls. The three indices of cerebral autoregulation—the breath-holding index (BHI), an autoregulation index calculated in phase II of the Valsalva maneuver (ASI), and cerebrovascular resistance measured in the second minute during the head-up tilting test (CVR_2-min)—all decreased in patients with epilepsy. ANS dysfunction correlated significantly with impairment of cerebral autoregulation (measured by BHI, ASI, and CVR_2-min), suggesting that the increased autonomic dysfunction in patients with epilepsy may augment the dysregulation of cerebral blood flow. Long-term epilepsy, a high frequency of seizures, and refractory epilepsy, particularly temporal lobe epilepsy, may contribute to advanced autonomic dysfunction and impaired cerebral autoregulation. These results have implications for therapeutic interventions that aim to correct central autonomic dysfunction and impairment of cerebral autoregulation, particularly in patients at high risk for sudden, unexplained death in epilepsy. Full article

We are overwhelmed by a deluge of data and, although its interpretation is challenging, fortunately, information technology comes to the rescue. One of the tools is artificial intelligence, allowing the identification of relationships between variables and their arbitrary classification. We focused on the assessment of both the remission of proteinuria and the deterioration of kidney function in patients with IgA nephropathy, comparing several methods of machine learning. It is of utmost importance to respond to subtle changes in kidney function, which will lead to a deceleration of the disease. This goal has been achieved by analyzing regression techniques, predicting the difference in serum creatinine concentration. We obtained the performance of the tested models which classified patients with high accuracy (Random Forest Classifier showed an accuracy of 0.8–1.0, Multi-Layer Perceptron an Area Under Curve of 0.8842–0.9035 and an accuracy of 0.7527–1.0) and regressors with a low estimation error (Decision Tree Regressor showed MAE 0.2059, RMSE 0.2645). We have demonstrated the impact of both model selection and input features on performance. Application of machine learning methods requires careful selection of models and assessed parameters. The computing power of modern computers allows searching for the models most effective in terms of accuracy. Full article

The development and implementation of the approaches of personalized medicine for disease prevention are still at infancy, although preventive activities in healthcare represent a key pillar to guarantee health system sustainability. There is an increasing interest in finding informative markers that indicate the disease risk before the manifestation of the disease (primary prevention) or for early disease detection (secondary prevention). Recently, the systematic collection and study of clinical phenotypes and biomarkers consented to the advance of Rehabilomics in tertiary prevention. It consents to identify relevant molecular and physiological factors that can be linked to plasticity, treatment response, and natural recovery. Implementation of these approaches would open avenues to identify people at high risk and enable new preventive lifestyle interventions or early treatments targeted to their individual genomic profile, personalizing prevention and rehabilitation. The integration of personalized medicine into prevention may benefit citizens, patients, healthcare professionals, healthcare authorities, and industry, and ultimately will seek to contribute to better health and quality of life for Europe’s citizens. Full article

Segmentation is crucial in medical imaging analysis to help extract regions of interest (ROI) from different imaging modalities. The aim of this study is to develop and train a 3D convolutional neural network (CNN) for skull segmentation in magnetic resonance imaging (MRI). 58 gold standard volumetric labels were created from computed tomography (CT) scans in standard tessellation language (STL) models. These STL models were converted into matrices and overlapped on the 58 corresponding MR images to create the MRI gold standards labels. The CNN was trained with these 58 MR images and a mean ± standard deviation (SD) Dice similarity coefficient (DSC) of 0.7300 ± 0.04 was achieved. A further investigation was carried out where the brain region was removed from the image with the help of a 3D CNN and manual corrections by using only MR images. This new dataset, without the brain, was presented to the previous CNN which reached a new mean ± SD DSC of 0.7826 ± 0.03. This paper aims to provide a framework for segmenting the skull using CNN and STL models, as the 3D CNN was able to segment the skull with a certain precision. Full article

IgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX^®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1^KI-CD89^Tg). Methods: The α1^KI-CD89^Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX^®). Serum levels of hIgA, hIgA1–sCD89, and mIgG–hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1–sCD89 and mIgG–hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1^KI-CD89^Tg mice, suggesting a possible role for it in the treatment of the disease. Full article

In Glioblastoma Multiforme (GBM), hypoxia is associated with radioresistance and poor prognosis. Since standard GBM treatments are not always effective, new strategies are needed to overcome resistance to therapeutic treatments, including radiotherapy (RT). Our study aims to shed light on the biomarker network involved in a hypoxic (0.2% oxygen) GBM cell line that is radioresistant after proton therapy (PT). For cultivating cells in acute hypoxia, GSI’s hypoxic chambers were used. Cells were irradiated in the middle of a spread-out Bragg peak with increasing PT doses to verify the greater radioresistance in hypoxic conditions. Whole-genome cDNA microarray gene expression analyses were performed for samples treated with 2 and 10 Gy to highlight biological processes activated in GBM following PT in the hypoxic condition. We describe cell survival response and significant deregulated pathways responsible for the cell death/survival balance and gene signatures linked to the PT/hypoxia configurations assayed. Highlighting the molecular pathways involved in GBM resistance following hypoxia and ionizing radiation (IR), this work could suggest new molecular targets, allowing the development of targeted drugs to be suggested in association with PT. Full article

Of children with recurrent wheezing in early childhood, approximately half go on to develop asthma. MicroRNAs have been described as excellent non-invasive biomarkers due to their prognostic utility. We hypothesized that circulating microRNAs can predict incident asthma and that that prediction might be modified by vitamin D. We selected 75 participants with recurrent wheezing at 3 years old from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Plasma samples were collected at age 3 and sequenced for small RNA-Seq. The read counts were normalized and filtered by depth and coverage. Logistic regression was employed to associate miRNAs at age 3 with asthma status at age 5. While the overall effect of miRNA on asthma occurrence was weak, we identified 38 miRNAs with a significant interaction effect with vitamin D and 32 miRNAs with a significant main effect in the high vitamin D treatment group in VDAART. We validated the VDAART results in Project Viva for both the main effect and interaction effect. Meta-analysis was performed on both cohorts to obtain the combined effect and a logistic regression model was used to predict incident asthma at age 7 in Project Viva. Of the 23 overlapped miRNAs in the stratified and interaction analysis above, 9 miRNAs were replicated in Project Viva with strong effect size and remained in the meta-analysis of the two populations. The target genes of the 9 miRNAs were enriched for asthma-related Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using logistic regression, microRNA hsa-miR-574-5p had a good prognostic ability for incident asthma prognosis with an area under the receiver operating characteristic (AUROC) of 0.83. In conclusion, miRNAs appear to be good biomarkers of incident asthma, but only when vitamin D level is considered. Full article

Myristic acid is identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Its significant decrease has been observed in patients with septic shock not responding to treatment. Another study has reported a close correlation of myristic acid levels with the outcome of severe trauma patients. Myristic acid concentrations were investigated in a cohort of septic patients and patients with Systemic Inflammatory Response Syndrome (SIRS) in 5 consecutive days following diagnosis and compared to healthy controls. The study population groups—Sepsis 34, SIRS 31, and Healthy Control 120 patients were included. Serum samples were analyzed using gas chromatography and mass spectrometry. The myristic acid levels in the Sepsis Group and SIRS Group were found to be significantly higher when compared to healthy controls. The serum concentration of myristic acid in septic patients with bacteraemia was higher than in septic patients without bacteraemia. Most patients with sepsis and SIRS had the highest levels of myristic acid within 24 h after an established diagnosis. Myristic acid should be considered as a new candidate marker of severe inflammation and sepsis. A simplified analysis and sufficient body of validated data are necessary steps towards the introduction of this metabolite into routine clinical practice. Full article

This research consists of two studies which aimed to: (1) evaluate the psychometric properties of a new self-report measure for the assessment of mentalizing, the Multidimensional Mentalizing Questionnaire (MMQ); and (2) investigate the ability of the instrument to discriminate between community and clinical populations. A sample of 349 participants (19% male, 81% female; M_age = 38.6, SD = 15.3) filled in the MMQ and other self-report measures, in order to assess the factor structure, reliability and some aspects of construct validity of the measure. Then, a clinical sample (N = 46; 52% male and 48% female; M_age = 33.33, SD = 12.257) and a community one (N = 50; 42% male and 58% female; M_age = 38.86, SD = 16.008) filled in the MMQ, to assess its clinical sensitivity. The factorial analysis identified six principal dimensions of the measure: reflexivity, ego-strength, relational attunement, relational discomfort, distrust, and emotional dyscontrol. The MMQ showed satisfactory psychometric properties and a theoretically relevant factor structure. Furthermore, significantly greater impairment in mentalizing was found in the clinical sample in respect of the community one. The findings are discussed in terms of clinical implications, emphasizing the usefulness of the MMQ in both research and clinical practice. Full article

Atypical hemolytic uremic syndrome (aHUS) is a rare disease triggered by dysregulation of the alternative complement pathway, consisting of a characteristic triad of nonimmune hemolytic anemia, thrombocytopenia, and renal failure. The risk of aHUS onset, recurrence, and allograft loss depends on the genetic background of a patient. We show a series of cases from a single family whose five members were affected by aHUS and presented distinct clinical outcomes. Next-generation sequencing revealed combined mutations in both complement factor H and membrane cofactor protein CD46. Out of eight siblings, aHUS affected three adult brothers, and, subsequently, affected two children of an unaffected sister. The first patient died due to aHUS, and two other brothers underwent successful kidney transplantation with no aHUS recurrence. The younger, 10-month-old child presented with a severe course of the disease with cardiac involvement and persistent hemolytic anemia limited by eculizumab, while the 2-year-old recovered completely on eculizumab. The study shows a highly variable disease penetrance. Full article

Background: Prior trials investigating the treatment of symptomatic osteoarthritis (OA) with hyaluronic-acid-derived products injections have provided optimistic results. The study was directed to assess the effectiveness of an innovative hyaluronic-acid-based hydrogel (Hymovis^®) in the treatment of symptomatic knee OA. Methods: A prospective, single-center, clinical trial was performed. Thirty-five patients with degenerative knee OA were included. Inclusion criteria were: age between 45–80, radiographic Kellgren grade II or III osteoarthritis, minimum 35 mm score on the Visual Analogue Scale (VAS), pain for at least 6 months and agreement to participate in the study. Patients received two injections at a one-week interval. The evaluator assessed the patients using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and VAS. Evaluation was performed before, at 2 and 6 months after the injections. Results: A significant improvement on the WOMAC Index pain subscale was observed at 6 months after the injection. At two months, pain subscale score decreased from 10.34 to 9.34. At six months, a significant decrement in pain parameters compared to baseline was observed (from 10.34 to 7.72; p = 0.0004). Median points on VAS significantly ameliorated after 6 months (from 74.2 to 57.3 cm; p < 0.0001). Regarding physical function, a statistically significant difference compared to baseline was observed at the end of the study (from 29.74 to 25.18; p = 0.0025). WOMAC Index stiffness component did not differ from baseline at any time during follow-up. Conclusions: Pain relief installed with a delayed on-set but had a prolonged duration. The novel hyaluronic acid-based hydrogel (Hymovis^®) had effective results, particularly after six months post-injections and offers a therapeutic advancement in the treatment of moderate to severe osteoarthritis. Full article

Familial hypercholesterolaemia (FH) is a common inherited cause of premature cardiovascular disease, but the majority of patients remain undiagnosed. The aim of this systematic review was to assess the effectiveness of interventions to systematically identify FH in primary care. No randomised, controlled studies were identified; however, three non-randomised intervention studies were eligible for inclusion. All three studies systematically identified FH using reminders (on-screen prompts) in electronic health records. There was insufficient evidence that providing comments on laboratory test results increased the identification of FH using the Dutch Lipid Clinic Network (DLCN) criteria. Similarly, using prompts combined with postal invitation demonstrated no significant increase in definite FH identification using Simon-Broome (SB) criteria; however, the identification of possible FH increased by 25.4% (CI 17.75 to 33.97%). Using on-screen prompts alone demonstrated a small increase of 0.05% (95% CI 0.03 to 0.07%) in identifying definite FH using SB criteria; however, when the intervention was combined with an outreach FH nurse assessment, the result was no significant increase in FH identification using a combination of SB and DLCN criteria. None of the included studies reported adverse effects associated with the interventions. Currently, there is insufficient evidence to determine which is the most effective method of systematically identifying FH in non-specialist settings. Full article

The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTA^TM, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTA^TM. Full article

Background: Searching through the COVID-19 research literature to gain actionable clinical insight is a formidable task, even for experts. The usefulness of this corpus in terms of improving patient care is tied to the ability to see the big picture that emerges when the studies are seen in conjunction rather than in isolation. When the answer to a search query requires linking together multiple pieces of information across documents, simple keyword searches are insufficient. To answer such complex information needs, an innovative artificial intelligence (AI) technology named a knowledge graph (KG) could prove to be effective. Methods: We conducted an exploratory literature review of KG applications in the context of COVID-19. The search term used was “covid-19 knowledge graph”. In addition to PubMed, the first five pages of search results for Google Scholar and Google were considered for inclusion. Google Scholar was used to include non-peer-reviewed or non-indexed articles such as pre-prints and conference proceedings. Google was used to identify companies or consortiums active in this domain that have not published any literature, peer-reviewed or otherwise. Results: Our search yielded 34 results on PubMed and 50 results each on Google and Google Scholar. We found KGs being used for facilitating literature search, drug repurposing, clinical trial mapping, and risk factor analysis. Conclusions: Our synopses of these works make a compelling case for the utility of this nascent field of research. Full article

Autism spectrum disorder (ASD) is associated with significant social, communication, and behavioral challenges. The insufficient number of trained clinicians coupled with limited accessibility to quick and accurate diagnostic tools resulted in overlooking early symptoms of ASD in children around the world. Several studies have utilized behavioral data in developing and evaluating the performance of machine learning (ML) models toward quick and intelligent ASD assessment systems. However, despite the good evaluation metrics achieved by the ML models, there is not enough evidence on the readiness of the models for clinical use. Specifically, none of the existing studies reported the real-life application of the ML-based models. This might be related to numerous challenges associated with the data-centric techniques utilized and their misalignment with the conceptual basis upon which professionals diagnose ASD. The present work systematically reviewed recent articles on the application of ML in the behavioral assessment of ASD, and highlighted common challenges in the studies, and proposed vital considerations for real-life implementation of ML-based ASD screening and diagnostic systems. This review will serve as a guide for researchers, neuropsychiatrists, psychologists, and relevant stakeholders on the advances in ASD screening and diagnosis using ML. Full article

How can the knowledge of probiotics and their mechanisms of action be translated into clinical practice when treating patients with diverticular disease and acute diverticulitis? Changes in microbiota composition have been observed in patients who were developing acute diverticulitis, with a reduction of taxa with anti-inflammatory activity, such as Clostridium cluster IV, Lactobacilli and Bacteroides. Recent observations supported that a dysbiosis characterised by decreased presence of anti-inflammatory bacterial species might be linked to mucosal inflammation, and a vicious cycle results from a mucosal inflammation driving dysbiosis at the same time. An alteration in gut microbiota can lead to an altered activation of nerve fibres, and subsequent neuronal and muscular dysfunction, thus favoring abdominal symptoms’ development. The possible role of dysbiosis and mucosal inflammation in leading to dysmotility is linked, in turn, to bacterial translocation from the lumen of the diverticulum to perivisceral area. There, a possible activation of Toll-like receptors has been described, with a subsequent inflammatory reaction at the level of the perivisceral tissues. Being aware that bacterial colonisation of diverticula is involved in the pathogenesis of acute diverticulitis, the rationale for the potential role of probiotics in the treatment of this disease becomes clearer. For this review, articles were identified using the electronic PubMed database through a comprehensive search conducted by combining key terms such as “gut microbiota”, “probiotics and gut disease”, “probiotics and acute diverticulitis”, “probiotics and diverticular disease”, “probiotics mechanism of action”. However, the amount of data present on this matter is not sufficient to draw robust conclusions on the efficacy of probiotics for symptoms’ management in diverticular disease. Full article

The microbiota has been reported to be correlated with carcinogenesis and cancer progression. However, its involvement in the pathology of mesothelioma remains unknown. In this study, we aimed to identify mesothelioma-specific microbiota using resected or biopsied mesothelioma samples. Eight mesothelioma tissue samples were analyzed via polymerase chain reaction (PCR) amplification and 16S rRNA gene sequencing. The operational taxonomic units (OTUs) of the effective tags were analyzed in order to determine the taxon composition of each sample. For the three patients who underwent extra pleural pneumonectomy, normal peripheral lung tissues adjacent to the tumor were also included, and the same analysis was performed. In total, 61 OTUs were identified in the tumor and lung tissues, which were classified into 36 species. Streptococcus australis and Ralstonia pickettii were identified as abundant species in almost all tumor and lung samples. Streptococcus australis and Ralstonia pickettii were found to comprise mesothelioma-specific microbiota involved in tumor progression; thus, they could serve as targets for the prevention of mesothelioma. Full article

Prostate cancer is among the most frequent cancers in men worldwide. Despite the fact that multiple therapeutic alternatives are available for its treatment, it is often discovered in an advanced stage as a metastatic disease. Prostate cancer screening is based on physical examination of prostate size and prostate-specific antigen (PSA) level in the blood as well as biopsy in suspect cases. However, these markers often fail to correctly identify the presence of cancer, or their positivity might lead to overdiagnosis and consequent overtreatment of an otherwise silent non-progressing disease. Moreover, these markers have very limited if any predictive value regarding therapy response or individual risk for therapy-related toxicities. Therefore, novel, optimally liquid biopsy-based (blood-derived) markers or marker panels are needed, which have better prognostic and predictive value than the ones currently used in the everyday routine. In this review the role of circulating tumour cells, extracellular vesicles and their microRNA content, as well as cellular and soluble immunological and inflammation- related blood markers for prostate cancer diagnosis, prognosis and prediction of therapy response is discussed. A special emphasis is placed on markers predicting response to radiotherapy and radiotherapy-related late side effects. Full article

Background: Multiple sclerosis (MS) is frequently characterized by a variety of clinical signs, often exhibiting little specificity. The diagnosis requires a combination of medical observations and instrumental tests, and any support for its objective assessment is helpful. Objective: Herein, we describe the application of thermal liquid biopsy (TLB) of blood plasma samples, a methodology for predicting the occurrence of MS with a noninvasive, quick blood test. Methods: TLB allows one to define an index (TLB score), which provides information about overall real-time alterations in plasma proteome that may be indicative of MS. Results: This pilot study, based on 85 subjects (45 MS patients and 40 controls), showed good performance indexes (sensitivity and specificity both around 70%). The diagnostic methods better discriminate between early stage and low-burden MS patients, and it is not influenced by gender, age, or assumption of therapeutic drugs. TLB is more accurate for patients having low disability level (≤ 3.0, measured by the expanded disability status scale, EDSS) and a relapsing–remitting diagnosis. Conclusion: Our results suggest that TLB can be applied to MS, especially in an initial phase of the disease when diagnosis is difficult and yet more important (in such cases, accuracy of prediction is close to 80%), as well as in personalized patient periodic monitoring. The next step will be determining its utility in differentiating between MS and other disorders, in particular in inflammatory diseases. Full article

The last decade saw extensive studies of the human gut microbiome and its relationship to specific diseases, including gallstone disease (GSD). The information about the gut microbiome in GSD-afflicted Russian patients is scarce, despite the increasing GSD incidence worldwide. Although the gut microbiota was described in some GSD cohorts, little is known regarding the gut microbiome before and after cholecystectomy (CCE). By using Illumina MiSeq sequencing of 16S rRNA gene amplicons, we inventoried the fecal bacteriobiome composition and structure in GSD-afflicted females, seeking to reveal associations with age, BMI and some blood biochemistry. Overall, 11 bacterial phyla were identified, containing 916 operational taxonomic units (OTUs). The fecal bacteriobiome was dominated by Firmicutes (66% relative abundance), followed by Bacteroidetes (19%), Actinobacteria (8%) and Proteobacteria (4%) phyla. Most (97%) of the OTUs were minor or rare species with ≤1% relative abundance. Prevotella and Enterocossus were linked to blood bilirubin. Some taxa had differential pre- and post-CCE abundance, despite the very short time (1–3 days) elapsed after CCE. The detailed description of the bacteriobiome in pre-CCE female patients suggests bacterial foci for further research to elucidate the gut microbiota and GSD relationship and has potentially important biological and medical implications regarding gut bacteria involvement in the increased GSD incidence rate in females. Full article

Psoriasis is a chronic inflammatory skin pathology of autoimmune origin and unknown etiology. There are various therapies for treating it, including a wide range of biopharmaceuticals indicated in moderate-to-severe psoriasis. Depending on their therapeutic target, they are classified as tumor necrosis factor inhibitors (anti-TNF) or cytokine inhibitors (interleukin-12, 23, and 17 antagonists). Although they have proved effective and safe, in clinical practice, many patients show a short- and long-term suboptimal response and even varying degrees of toxicity. This variability in response may be influenced by genetic factors, such as polymorphisms in the genes involved in the pathological environment, metabolism or mechanism of action of the drug that could affect the effectiveness and toxicity of biological therapies. This review assesses pharmacogenetic studies of the impact of genetic factors on response to biopharmaceuticals and toxicity in patients diagnosed with moderate-to-severe psoriasis. The results suggest that polymorphisms detected in the HLA genes, in genes that encode cytokines (TNF, IL genes, TNFAIP3), transporters (PDE3A-SLCO1C1, SLC12A8), receptors (TNFRSF1B, CD84, FCGR2A and FCGR3A, IL17RA, IL23R, TLR genes, PGLYRP4) and associated proteins (TNFAIP3, LY96, TIRAP, FBXL19), as well as other genes implicated in the pathogenesis of psoriasis (CDKAL1, CARD14, PTTG1, MAP3K1, ZNF816A, GBP6, CTNNA2, HTR2A, CTLA4, TAP1) can be used in the future as predictive markers of treatment response and/or toxicity with biological therapies in patients diagnosed with moderate-to-severe psoriasis, tailoring treatment to the individual patient. Full article

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type. Full article

Objective: In this pilot clinical study we investigated the effect on blood pressure (BP) of two community-based exercise training programs of high (HIT) vs. low-moderate intensity (LMIT) in hypertensive individuals receiving at least one antihypertensive drug. Methods: The study included two phases of physical exercises based on 1-h session, 3 days/week for 12 and 16 weeks, respectively, separately by a 7-week resting period. Each phase was preceded by a four-week conditioning training period. According to the average maximal heart rate at baseline, participants were randomized to HIT (80–90%), LMIT (50–70%) or no-exercise (control). Heart rate was monitored during workout and BP profiles were registered by ambulatory BP monitoring at the beginning and end of each phase. Results: Of 60 individuals randomized, 44 completed the study (HIT, n = 10; LMIT, n = 16; controls, n = 18). BP levels were significantly reduced after the second phase for both LMIT (SBP −3.1 mmHg, DBP −2.4 mmHg) and HIT (SBP −10.8 mmHg, DBP −8.3 mmHg). Similar levels of improvement were also found in daytime and night-time BP. Mean attendance of the prescribed training sessions was 87.4 ± 6.2% for HIT and 87.4 ± 5.3% for LMIT during the first phase and 84.1 ± 5.0% and 85.2 ± 5.9% during the second phase, respectively (p = 0.047). Conclusion: Both HIT and LMIT exercise training programs reduced BP but the HIT modality showed a lower rate of compliance with proposed training schedule. Intensity of training should be individually prescribed to improve tolerance to more high intensity exercises. Full article