Background Research on the mental health of students in health disciplines mainly focuses on psychological distress and nursing and medical students. This study aimed to investigate the psychological well-being and distress and related factors among undergraduate students training in eight different health-related tracks in Geneva, Switzerland. Methods This cross-sectional study used established self-filled scales for anxiety, depression, stress, psychological well-being, and study satisfaction. Descriptive statistics and hierarchical regression analyses were applied. Results In October 2019, out of 2835 invited students, 915 (32%) completed the survey. Lower academic satisfaction scores were strongly associated with depression (β=-.26, p<.001), anxiety (β=-.27, p<.001), and stress (β=-.70, p<.001), while higher scores with psychological well-being (β=.70, p<.001). Being female was strongly associated with anxiety and stress but not with depression or psychological well-being. Increased age was associated with enhanced psychological well-being. The nature of the academic training had a lesser impact on mental health and the academic year none. Conclusion Academic satisfaction strongly predicts depression, anxiety, stress, and psychological well-being. Training institutions should address the underlying factors that can improve students’ satisfaction with their studies while ensuring that they have access to psychosocial services that help them cope with mental distress and enhance their psychological well-being.

It is well known that low back pain (LBP) prevalence is high during the course of school age children’s lives. However, literature concerning the initial onset of back pain between ages of 3 and 11 years remains scarce. The present study aimed to analyze the prevalence of LBP in kindergarten and primary school students. 278 (9.9±2.1 years old; 52.2% girls) students from two public kindergarten and primary schools in Valencia, Spain participated in this cross-sectional study. The Nordic questionnaire on LBP was used to ask questions related to the duration of LBP symptoms over time. The lifetime prevalence of LBP was 47.5% (n = 132), a last year prevalence of 44.2% (n = 123), and a last week prevalence of 18.8% (n = 50) was reported. Boys and girls reached lifetime prevalence of 52.3% (n = 64) and 47.7% (n = 82) (χ2 = 1.978, p = .099), respectively. By age group, lifetime episodes of LBP also showed a higher prevalence with increasing age (χ2 = 32.637; p &lt; .001). In summary, our findings suggest that LBP increases with age. In addition, our results further strengthen the evidence that LBP onset could start as young as 10-years-old.

Exercise can be hypothesized to play an important role in NAFLD treatment by changing the oral bacterial flora and in the mechanism underlying periodontal disease. We performed salivary component analysis before and after an exercise regimen, and genome analysis of the oral bacterial flora to elucidate the underlying mechanism. Obese middle-aged men with NAFLD and periodontal disease were allocated to 12-week exercise (n=49) or dietary restriction (n=21) groups. We collected saliva to compare the oral microflora; performed predictive analysis of metagenomic functions; and measured the salivary immunoglobulin A, cytokine, bacterial lipopolysaccharide (LPS), and lactoferrin concentrations. The exercise group showed improvements in clinical indices of oral environment. Salivary component analysis revealed significant reductions in LPS, and lactoferrin during the exercise regimen. Diversity analysis of oral bacterial flora revealed higher alpha- and beta-diversity after the exercise regimen. Analysis of the microbial composition revealed that the numbers of Campylobacter (+83.9%), Corynebacterium (+142.3%), Actinomyces (+75.9%), and Lautropia (+172.9%) were significantly higher and that of Prevotella (−28.3%) was significantly lower. The findings suggest that an exercise regimen improves the oral environment of NAFLD patients by increasing the diversity of the oral microflora and reducing the number of periodontal bacteria that produce LPS and its capability.

Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location and disease endotype. We found sexual dimorphism in expression of COVID-19 genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2 and TMPRSS4, were highly upregulated in both sexes. Overall, changes in COVID-19 gene expression were specific to Th2 high molecular endotype of asthma, and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors correlated with loss of club and ciliated cells in Th2 high asthma, while the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) associated with an increase in goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype and changes in epithelial heterogeneity as factors underlying asthmatic susceptibility, or lack thereof, to COVID-19.

To quantify the time-varying reproduction number (Rt) for Malaysia using the COVID-19 incidence data., we used data the from the Johns Hopkins University Center for Systems Science and Engineering (JHU CCSE) Coronavirus repository. Day 1 was taken from the first assumed local transmission of COVID-19. Data was split into four intervals: a) Interval 1: from Day 1 to Day 10 MCO 1, b) Interval 2: from Day 1 to Day 10 MCO 2, c) Interval 3: from Day 1 to Day 10 MCO 3 and d) Interval 4: from Day 1 to Day 10 MCO 4. We estimated the Rt using the EpiEstim package. The means for Rt at Day 1, Day 5 and Day 10 for all MCOs ranged between 0.665 to 1.147. The average Rt gradually decreased in MCO 1 and MCO 2. However, Rt increased in MCO 3 before stabilized around 0.8 in MCO 4. MCO 1 and MCO 2 which were stricter coincide with the gradual reduction of Rt. However, the more relaxed MCO 3 and MCO 4 correspond to a slight increase in the Rt before it stabilized.

The prevalence of type-2 diabetes mellitus (T2D) is increasing worldwide and there are no long-term preventive strategies to stop this growth. Emerging research shows that perturbations in the gut microbiome significantly contribute to the development of T2D, while microbiome modulators may be beneficial for T2D prevention. However, microbiome modulators that are effective, safe, affordable, and able to be integrated daily in the diet are not yet available. Based on our previous pro- and prebiotic studies, we developed a novel synbiotic yogurt comprised of human-origin probiotics and plant-based prebiotics and investigated its impact on diet- and streptozotocin-induced T2D in mice. We compared the effects of our synbiotic yogurt to those of a commercially-available yogurt (control yogurt). Interestingly, we found that feeding of this synbiotic yogurt significantly reduced the development of hyperglycemia (diabetes) in response to high-fat diet feeding and streptozotocin compared to milk-fed controls. Surprisingly, the control yogurt exacerbated diabetes progression. Synbiotic yogurt beneficially modulated the composition of gut microbiota compared to milk; conversely, the control yogurt negatively modulated the gut microbiota by significantly increasing the abundance of detrimental bacteria like Proteobacteria and Enterobacteriaceae. In addition, the synbiotic yogurt protected intact pancreatic islet morphology compared to the milk control, while the commercial yogurt demonstrated worse effects on pancreatic physiology. These results suggest that our newly developed synbiotic yogurt protects against diabetes in mice and can be used as a modality to prevent diabetes progression.

Background: The t (2; 5) chromosomal rearrangement and resulting nucleophosmin (NPM1) -ALK fusion was first observed in 1994 in anaplastic large cell lymphoma (ALCL), a T-cell lymphoma responsive to cyclophosphamide, abriblastine, vincristine and prednisone in approximately 80% of cases; refractory cases usually respond favorably to brentuximab-vedotin. These treatments are regarded as a bridge to allogeneic hematopoietic stem cell transplantation (allo-SCT). Nowadays, transplant procedures and monitoring of chemotherapy patients proceed very slowly because the SARS-CoV-2 pandemic has heavily clogged the hospitals in all countries. Results: A 40-year-old Caucasian woman was first seen at our clinical center in June 2020. She had ALCL ALK +, a history of failure to two previous therapeutic lines and was in complete remission after 12 courses of Brentuximab, still pending allo-SCT after two failed donor selection. Facing of a new therapeutic failure, we requested the Italian drug regulatory agency, and obtained the authorization, to administer 250 mg twice a day of Crizotinib, a drug incomprehensibly not registered for ALCL ALK +. Conclusions: The response to Crizotinib was optimal, since no adverse event occurred, and CT-PET persisted negative; this drug has proved to be a valid bridge to allo-SCT

The earlier analytical analysis (part A) of the Susceptible-Infectious-Recovered (SIR) epidemics model for a constant ratio k of infection to recovery rates is extended here to the semi-time case which is particularly appropriate for modeling the temporal evolution of later (than the first) pandemic waves when a greater population fraction from the first wave has been infected. In the semi-time case the SIR model does not describe the quantities in the past; instead they only hold for times later than the initial time t=0 of the newly occurring wave. Simple exact and approximative expressions are derived for the final and maximum values of the infected, susceptible and revovered/removed population fractions as well the daily rate and cumulative number of new infections. It is demonstrated that two types of temporal evolution of the daily rate of new infections j(tau) occur depending on the values of k and the initial value of the infected fraction I(0)=eta: in the decay case for k > 1-2 eta the daily rate monotonically decreases at all positive times from its initial maximum value j(0)=eta (1-eta). Alternatively, in the peak case for k<1-2 eta the daily rate attains a maximum at a finite positive time. By comparing the approximated analytical solutions for j(tau) and J(tau) with the exact ones obtained by numerical integration, it is shown that the analytical approximations are accurate within at most only 2.5 percent. It is found that the initial fraction of infected persons sensitively influences the late time dependence of the epidemics, the maximum daily rate and its peak time. Such dependencies do not exist in the earlier investigated all-time case.

Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases including The Cancer Genome Atlas (TCGA) were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 LoF variants were most often associated with uterine carcinoma. Two DPP9 intronic SNPs that have been associated with lung fibrosis and COVID-19 were not associated with liver fibrosis or cancer. All four DPP4-like genes were overexpressed in liver tumours and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients.. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is essential for human survival and the DPP4 protease family is important in cancer pathogenesis.

Sound signals from the respiratory system are largely the harbingers of human health. Early diagnosis of respiratory tract diseases is of great importance as it creates irreversible effects on human health when delayed. This diagnostic in the medical world has been made possible thanks to machine learning and signal processing analysis. The coronavirus epidemic, which is in question today and deeply shakes the whole world, has been revealed the importance of this issue even more. In terms of the coronavirus pandemic, it has become the focus of researchers to differentiate symptoms from similar diseases such as normal flu or influenza. Among these symptoms, the difference in cough sound has played a distinctive role in the proposed study. Several pioneering studies have proven that almost two-thirds of people who get corona have a dry cough. At this stage, the information of studies based on cough constitutes the main framework of our study. On the other hand, the basis of this study is based on machine learning algorithms. Clinical data collected under the supervision of doctors in a reliable environment was used as dataset. This dataset consists of 16 subjects suspected of the coronavirus with a specific patient demographic. In this study, using the polymerase chain reaction (PCR) test, suspected subjects were divided into two groups as negative and positive. The negative and positive labels represent the patient with non-COVID and with a COVID-19 cough respectively. Using the 3D plot or waterfall representation of the signal frequency spectrum, the salient features of the cough data are revealed. In this way, COVID-19 can be differentiated from other coughs by applying effective feature extraction and classification techniques. Power Spectral Density (PSD) based on Short Time Fourier Transform (STFT) and Mel Frequency Cepstral Coefficients (MFCC) were chosen as the efficient feature extraction method. Finally, among the classification techniques the Support Vector Machine (SVM) algorithm, was applied to the processed signals in order to identify and classify COVID-19 cough. In terms of results evaluation, the cough of subjects with COVID-19 has obtained with 95.86% classification accuracy thanks to the RBF kernel function of SVM and the MFCC method. In other words, the diagnosis of COVID-19 coughs was obtained with 98.6% and 91.7% sensitivity and specificity measures respectively.

The current article examined stoma self-care and health-related quality of life in patients with drainage enterostomy, describe clinical and sociodemographic variables and analyze the relations between all of them. Trained interviewers collected data using a standardized form that queried sociodemographic and clinical variables, collected from the electronic medical record, in addition to the Specific Self-Care for Ostomized Patients Questionnaire (CAESPO) and Stoma Quality of life (S-QoL) from January 2016 to January 2017. This was a multicenter, cross sectional study conducted in four hospitals of the province of Castellon (Spain) where 120 participants were studied. Significant differences were found in Self Care according to sex (p = .043); married participants show higher score (p < .01); also, significant differences according to work activity were observed (p < .01). Regarding the clinical variables, differences were observed according to the autonomy of care, the presence of complications in the stoma, the use of irrigation and the type of effluent (p < .01). We can highlight the importance of the skills related to self-care by ostomized patients has for a good level of quality of life related to health. In this learning process, the figure of the stoma therapist plays a very important role.

Background. Neoplastic diseases and infections have become the leading causes of death in SLE in recent decades. Cancers and infections were also precipitating factors in the development of catastrophic APS. Case summary. We describe two patients: one of them had definite antiphospholipid syndrome (APS) and melanoma and the other had definite systemic lupus erythematosus (SLE) with APS, melanoma, infiltrative tuberculosis and severe Herpes Zoster (HZ). Management of patients with SLE concurrent with APS is a rather difficult task in rheumatology practice. In addition to kidney damage and cardiovascular disease, infections and malignancies are a significant cause of death in this cohort. The risk of malignancy in SLE is of considerable interest, since the immune and genetic pathways underlying the pathogenesis of this disease, as well as the immunosuppressive therapy, can significantly alter the risk. Both patients still had reliable APS, confirmed by triple-positive aPL. Both were at high risk of thrombosis. Patients ' adherence to treatment with direct oral anticoagulants and relapse of thrombosis on the background of rivaroxaban were noted. Conclusion. The cases where cancer or tuberculosis develops in the presence of rheumatic diseases are not so common and complicate the possibilities of therapeutic approaches, limiting the use of drugs that are not regulated by clinical recommendations.

Sjogren syndrome (SS) is an autoimmune disease that involves salivary and lacrimal glands. There are rare articles describing hypohidrosis or anhidrosis in SS patients. Little is known about the histologic findings seen in patients with SS who do not report decreased sweating. We analyzed skin samples from 31 patients with SS who had undergone skin biopsies for reasons not related to SS. We assessed the number, distribution and pathologic changes within and around the eccrine ducts, glands and acrosyringia. The composition of the inflammatory infiltrate was additionally accessed utilizing immunohistochemical stains. Overall, in 60% of cases we observed some degree of inflammation. In virtually all cases the inflammatory infiltrate was located around the eccrine ducts at a distance from the non-SS pathology. It was mainly composed of CD3+ T cells with increasing number of B and plasma cells as periductal inflammation intensified. This study is the first histologic analysis of asymptomatic skin in patients with SS. It demonstrates the presence of skin involvement in the majority of SS patients. Our results emphasize the importance of systematic skin evaluation in this category of patients as well as counseling, early preventive measurements and timely treatment when indicated.

The constitutively active tyrosine kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene is not destroyed, lifelong oral medication is essential, even though this trigger adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the emergence of CRISPR technology can offer a definitive treatment based on its capacity to disrupt coding sequences. This review describes CML disease and the main advances in the genome-editing field by which it may be treated in the future.

Aim: Sialoliths are salivary gland calcifications that mainly affect submandibular and parotid glands. They are detected incidentally on dental panoramic radiographs. This study aimed to determine the prevalence of sialoliths in a Lebanese sample and evaluate the site, gender and age distribution of such findings. Methods: In this retrospective study, 500 digital panoramic radiographs, belonging to 219 males and 281 females aged 18-88 years, were examined to identify sialoliths seen as radiopacities in the parotid, submandibular and sublingual glands regions. Findings were analyzed statistically using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N.Y., USA). Descriptive statistics were presented and Chi-square tests and Spearman correlation coefficient were used to assess relationships between sialoliths and gender, age and site. Statistical significance was set at p=0.05. Results: In our sample of 500 radiographs, sialoliths were identified in 15 (3%). Submandibular sialoliths were the most common (1.8%) followed by parotid sialoliths (1.2%); no sublingual sialoliths were detected. Females were slightly more affected by submandibular sialoliths while males had higher prevalence of parotid sialoliths. No significant age or gender predilections were detected. Conclusion: Identifying sialoliths on panoramic radiographs by dental professionals is essential to avoid possibility of confusion with other soft tissue calcifications very common in the head and neck regions.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The interferons (IFNs) were discovered in 1957, and recombinant IFN-β-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for MS in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN-β-1a phase 3 trial was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN-β-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN-β-1a is associated with an increased incidence of injection site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians’ ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and monitoring. MRI studies show that treatment with IFN-β-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN-β-1a, several high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events. For some subpopulations of patients, including pregnant women, the safety profile of IFN-β formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate therapeutic opportunities for IFN-β in the treatment of viral infections such as COVID-19.

Objectives: There are limited data regarding the efficacy of methylprednisolone in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation. We aimed to determine whether methylprednisolone increases the number of ventilator-free days (VFDs) among these patients. Design: Retrospective single-center study Setting: Intensive care unit Patients: All patients with ARDS due to confirmed SARS-CoV-2 infection and requiring invasive mechanical ventilation between 1 March and 29 May 2020 were included Interventions: None Measurements and Main Results: The primary outcome was ventilator-free days (VFDs) during the first 28 days, defined as being alive and free from mechanical ventilation. The primary outcome was analyzed with competing-risks regression based on Fine and Gray’s proportional subhazards model. Death before day 28 was considered to be the competing event. A total of 77 patients met the inclusion criteria. Thirty-two patients (41.6%) received methylprednisolone. The median dose was 1 mg.kg-1 (IQR: 1-1.3 mg.kg-1) and median duration of 5 days (IQR:5-7 days). Patients who received methylprednisolone had a mean 18.8 VFDs (95% CI, 16.6-20.9) during the first 28 days vs. 14.2 VFDs (95% CI, 12.6-16.7) in patients who did not receive methylprednisolone (difference, 4.61; 95% CI, 1.10-8.12; P = 0.001). In the multivariable competing-risks regression analysis and after adjusting for potential confounders (ventilator settings, prone position, organ failure support, severity of the disease, tocilizumab, and inflammatory markers), methylprednisolone was independently associated with a higher number of VFDs (subhazards ratio: 0.10, 95%CI: 0.02-0.45; p=0.003). Hospital mortality did not differ between the two groups (31.2% vs. 28.9%, p=0.82). Hospital length of stay was significantly shorter in the methylprednisolone group (24 days [IQR:15-41 days] vs. 37 days [IQR:23-52 days], p=0.046). The incidence of positive blood cultures was higher in patients who received methylprednisolone (37.5% vs. 17.8%, p=0.052). However, 91% of patients who received methylprednisolone also received tocilizumab. The number of days with hyperglycemia was similar in the two groups. Conclusions: Methylprednisolone was independently associated with increased VFDs and shortened hospital length of stay. The combination of methylprednisolone and tocilizumab was associated with a higher rate of positive blood cultures. Further trials are needed to evaluate the benefits and safety of methylprednisolone in moderate or severe COVID-19 ARDS.

Childhood overweight and obesity is a worldwide public health issue. Our objective was to describe planned, ongoing and completed randomized controlled trials (RCTs) designed for the prevention of obesity in early childhood. Two databases (World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov) were searched to identify RCTs with the primary aim of preventing childhood obesity and at least one outcome related to child weight. Interventions needed to start in the first two years of childhood or earlier, continue for at least 6 months postnatally, include a component related to lifestyle or behaviors, and have a follow up time of at least 2 years. We identified 29 unique RCTs, implemented since 2008, with most being undertaken in high income countries. Interventions ranged from advice on diet, activity, sleep, emotion regulation and parenting education through individual home visits, clinic-based consultations or group education sessions. Eleven trials have published data on child weight related outcomes to date, though most were not sufficiently powered to detect significant effects. Many trials detected improvements in practices such as breastfeeding, screen time and physical activity in the intervention groups compared to the control groups. Further follow-up of ongoing trials is needed to assess longer-term effects.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Incidence of autoimmune diseases increases. Antinuclear antibodies (ANA) testing is a critical tool for their diagnosis. However, ANA prevalence in health increased over last decades, especially among young people. ANA in health occur in low concentrations, with prevalence up to 50% in some populations, which demands a cutoff revision. The review deals with origin and probable physiological or compensatory function of ANA in health, according to the concept of immunological clearance, theory of autoimmune regulation of cell functions and the concept of functional autoantibodies. Considering ANA titers ≤1:320 as a serological marker of autoimmune diseases seems inappropriate. The role of anti-DFS70/LEDGFp75 autoantibodies is highlighted as possible anti-risk biomarker for autoimmune rheumatic disorders. ANA prevalence in health is different in various regions due to several underlying causes discussed in the review, all influencing in additive combinations according to the concept of the mosaic of autoimmunity. Not only titer, but the HEp-2 IFA staining patterns, like AC-2, is also important. Accepting autoantibodies as a kind of bioregulators, not only upper, but also lower borders of their normal range should be determined. Not only their excess, but also lack of them or “autoimmunodeficiency” could be a reason of disorders.

Objectives- We prospectively analyzed children with acute chest pain and clinical suspicion of pneumothorax (PNX) evaluated at the pediatric Emergency Department. Methods- After clinical examination and before Chest X-Ray, children underwent LUS to evaluate the presence of PNX. We enrolled 70 children, 13 (18,57%) received a final diagnosis of PNX. Results- In all 13 (100%) patients LUS showed the “bar-code sign”, the absence of lung sliding and the absence of B lines while in 12 (92,3%) there was the lung point, giving a diagnosis of PNX. All cases had PNX features on CXR. The “bar-code sign”, the absence of lung sliding and the absence of B lines had a sensitivity of 100% and a specificity of 100%. The “bar-code sign” had a positive predictive value of 100% and a negative predictive value of 100% for the detection of PNX. Conclusions- LUS is highly accurate in detecting or excluding pneumothorax in children with acute chest pain evaluated in the pediatric emergency department.

Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s progression markers initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explain in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest (256) and smallest (-178) effect sizes measured as beta values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induces expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.

The thyroid gland secretes essential hormones for the growth regulation and the metabolic activity of the body. Thyroid dysfunction includes many conditions that can indirectly affect dental treatments. Therefore, the practitioner must be aware of these pathologies and their signs and symptoms in order to elaborate specific dental treatment plans, thus avoiding any per- and/or postoperative complications. Moreover, the dentist can help in the screening of undiagnosed thyroid dysfunction among patients.

Extracorporeal shock wave therapy (ESWT) is a well investigated and widely used treatment modality for a number of musculoskeletal disorders. A limitation of ESWT is its potential painfulness at higher, clinically relevant energy flux density (EFD), which may limit its applicability and, thus, effectiveness. Various studies in the literature demonstrated that neither application of a higher number of extracorporeal shock waves with lower EFD nor use of local anesthesia may solve this problem. Based on the results of several other studies in the literature it is hypothesized here that in patients suffering from musculoskeletal disorders that can be treated with ESWT, pretreatment with a pulsed, high power laser with a wavelength of 904 or 905 nanometers (hereafter: "laser pretreatment") does not only allow to apply higher EFDs in subsequent ESWT but actually results in faster and/or better treatment outcome than ESWT without laser pretreatment. Accordingly, it is hypothesized here that combining ESWT with laser pretreatment leads to synergistic effects and, thus, is superior to either treatment modality alone. Confirming this hypothesis in preclinical and clinical research may raise significance and increase the use of ESWT in physical and rehabilitation medicine, with immediate benefit for patients.

Introduction Early prediction of long term outcomes in patients resuscitated after cardiac arrest (CA) is still challenging. Guidelines suggested a multimodal approach combining multiple predictors. We evaluated whether the combination of the electroencephalography (EEG) reactivity, somatosensory evoked potentials (SSEPs) cortical complex and Gray to White matter ratio (GWR) on brain computed tomography (CT) at different temperatures could predict survival and good outcome at hospital discharge and after six months. Methods We performed a retrospective cohort study including consecutive adult, non-traumatic patients resuscitated from out-of-hospital CA who remained comatose on admission to our intensive care unit from 2013 to 2017. We acquired SSEPs and EEGs during the treatment at 36°C and after rewarming at 37°C, Gray to white matter ratio (GWR) was calculated on the brain computed tomography scan performed within six hours of the hospital admission. We primarily hypothesized that SSEP was associated with favorable functional outcome at distance and secondarily that SSEP provides independent information from EEG and CT. Outcomes were evaluated using the Cerebral Performance Category (CPC) scale at six months from discharge. Results Of 171 resuscitated patients, 75 were excluded due to missing of data or uninterpretable neurophysiological findings. EEG reactivity at 37 °C has been shown the best single predictor of good outcome (AUC 0.803) while N20P25 was the best single predictor for survival at each time point. (AUC 0.775 at discharge and AUC 0.747 at six months follow up) Predictive value of a model including EEG reactivity, average GWR, and SSEP N20P25 amplitude was superior (AUC 0.841 for survival and 0.920 for good outcome) to any combination of two tests or any single test. Conclusion Our study, in which life-sustaining treatments were never suspended, suggests SSEP cortical complex N20P25, after normothermia ad off sedation, is a reliable predictor for survival at any time. When SSEP cortical complex N20P25 is added into a model with GWR average and EEG reactivity, the predictivity for good outcome and survival at distance is superior than each single test alone.

Metabolic disorders, metabolic syndrome and non-alcoholic fatty liver disease, and depression are those of the most common and debilitating disorders worldwide that often coexist further increasing mortality risks. Although the exact mechanisms underlying this association are poorly known, several hypotheses have been proposed: antipsychotic medication and antidepressants use, diet and physical activity or any other lifestyle factors. However, the high co-occurrence rate of depression and metabolic disorders suggests a possible pathophysiological overlap. In this paper I review several raised mechanisms for this overlap which are the hypothalamic-pituitary-adrenal axis dysregulation, immune alterations with chronic inflammation, as well as oxidative stress. In my view, there is one common thread running through all the aforementioned areas of pathophysiology which is microbiota alteration. So far, several possible interventions in our microbiota have been introduced into clinical practice - dietary and other lifestyle changes, supplementation with prebiotics or probiotics, fecal microbiota transplantation – but with vague indications. A better characterization of the above associations may represent a critical step at phenotyping, and a more targeted approach to the treatment of both depressive and metabolic disorders. At the end of the paper, I give several practical applications for future studies.

Effective biomarkers are essential to the early diagnosis of non-small cell lung cancer (NSCLC). Herein, a retrospective study of 49 newly diagnosed and recurrent NSCLC patients, 31 patients with benign pulmonary disease and 24 healthy volunteers was conducted, to evaluate the diagnostic value of circulating rare cells for NSCLC. The expression of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in peripheral blood were measured by subtraction enrichment-immunostaining-fluorescence in situ hybridization (SE-iFISH). The level of CTCs (P＜0.001) and CTECs (P＜0.001) was significantly higher in NSCLC group than that in benign pulmonary disease group. The proportion of small CTCs (P＜0.001) and CTECs (P＜0.0001) significantly increased from benign lung disease individuals to NSCLC patients. The AUC of ROC curves of total CTCs and CTECs were 0.815 (95%CI: 0.722~0.907), 0.739 (95%CI: 0.618~0.860), respectively. The cut-off values for discriminating NSCLC with benign lung disease patients were total CTCs 11.5 units/6ml and total CTECs 10.5 units/6ml, with sensitivity and specificity being 67.3% and 83.9%, 77.6% and 77.4%, respectively. When CTCs and CTECs were combined, predictive value significantly increased to 82.6% as measured by the area under the curve. Small CTCs and triploid CTCs had high positive predictive value (PPV) and positive likelihood ratio (LR+) of the diagnosis of NSCLC in early stage. CTCs and CTECs can not only be used as new biomarkers for the diagnosis of NSCLC, but can also improve diagnostic performance of the early stage NSCLC. Moreover, the combined examination of CTCs and CTECs is be superior to the single.

Introduction: We describe the clinical features and inpatient trajectories of older adults hospitalized with COVID-19, and explore relationships with frailty. Methods: This retrospective observational study included older adults admitted as an emergency to a University Hospital who were diagnosed with COVID-19. Patient characteristics and hospital outcomes, primarily inpatient death or death within 14 days of discharge, were described for the whole cohort and by frailty status. Associations with mortality were further evaluated using Cox Proportional Hazards Regression (Hazard Ratio [HR], 95% Confidence Interval). Results: 214 patients (94 women) were included of whom 142 (66.4%) were frail with a median Clinical Frailty Scale (CFS) score of 6. Frail compared to non-frail patients were more likely to present with atypical symptoms including new or worsening confusion (45.1% vs 20.8%, p<0.001) and were more likely to die (66% vs 16%, p=0.001). Older age, being male, presenting with high illness acuity and high frailty were independent predictors of death and a dose-response association between frailty and mortality was observed (CFS 1-4: reference; CFS 5-6: HR 1.78, 95% CI 0.90, 3.53; CFS 7-8: HR 2.57, 95% CI 1.26, 5.24). Conclusions: Clinicians should have a low threshold for testing for COVID-19 in older and frail patients during periods of community viral transmission and diagnosis should prompt early advanced care planning.

Three cohorts including the Fire Department of the City of New York (FDNY), the World Trade Center Health Registry (WTCHR), and the General Responder Cohort (GRC), each funded by the World Trade Center Health Program have reported associations between WTC-exposures and cancer. Results have generally been consistent with effect estimates for excess incidence for all cancers ranging from 6 to 14% above background rates. Pooling would increase sample size and de-duplicate cases between the cohorts. Pooling required time consuming steps: obtaining IRB approvals and legal agreements from entities involved; establishing an honest broker for managing the data; de-duplicating the pooled cohort files; applying to State Cancer Registries (SCRs) for matched cancer cases; and finalizing analysis data files. Obtaining SCR data use agreements ranged from 6.5 to 114.5 weeks with six states requiring >20 weeks. Records from FDNY (n=16,221), WTCHR (n=29,372), and GRC (n=33,427) were combined de-duplicated resulting in 69,102 unique individuals. Overall, 7,894 cancer tumors were matched to the pooled cohort, increasing the number cancers by as much as 58% compared to previous analyses. Pooling resulted in a coherent resource for future research for studies on rare cancers and mortality, with more representative of occupations and WTC- exposure.

The internationals guidelines about food intolerances, allergy and immunity provide for rigorous steps in which ultrasonography is not provided. However there is evidence in literature about an ancillar role of ultrasonography in these conditions. In this report we analyze the main pathologies with allergic or immune pathogenesis

ST-elevation myocardial infarction (STEMI) remains one of the leading causes of morbidity and mortality worldwide. The identification of novel metabolic and imaging biomarkers could unveil key pathophysiological mechanisms at the molecular level and promote personalized care in patients with acute coronary syndromes. We studied 38 patients with STEMI who underwent primary percutaneous coronary intervention and thrombus aspiration. We sought to correlate serum ceramide levels with micro-CT quantified aspirated thrombus volume and relevant angiographic outcomes, including modified TIMI thrombus grade and pre- or post-procedural TIMI flow. Higher ceramide C16:0 levels were significantly, but weakly correlated with larger aspirated thrombus volume (Spearman r=0.326, p=0.046), larger intracoronary thrombus burden (Nagelkerke R2=0.236, p=0.030) and worse pre- and post-procedural TIMI flow (Nagelkerke R2=0.210; p=0.049 and Nagelkerke R2=0.277; p=0.039, respectively). Ceramides C24:0 and C24:1 were also significantly associated with larger intracoronary thrombus burden (Nagelkerke R2=0.311; p=0.008 and Nagelkerke R2=0.423; p=0.001, respectively). In conclusion, serum ceramide levels (mainly C16:0 and C24:1) were higher among patients with larger intracoronary and aspirated thrombus burden. This suggests that quantification of serum ceramides might improve risk-stratification of patients with STEMI and facilitate a more individualized approach in everyday clinical practice.

The aim of this study was to develop and validate a predictive early tooth loss multivariable model for periodontitis patients before periodontal treatment. A total of 544 patients seeking periodontal care at a university dental hospital were enrolled in the study. Teeth extracted after periodontal diagnosis and due to periodontal reasons were recorded. Clinical and sociodemographic variables were analyzed, considering the risk of short-term tooth loss. This study followed the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines for development and validation, with two cohorts considered as follows: 455 patients in the development phase and 99 in the validation phase. As a result, it was possible to compute a predictive model based on tooth type and clinical attachment loss. The model explained 25.3% of the total variability and correctly ranked 98.9% of the cases. The final reduced model area under the curve (AUC) was 0.809 (95% Confidence Interval (95% CI): 0.629 - 0.989) for the validation sample and 0.920 (95% CI: 0.891 - 0.950) for the development cohort. The established model presented adequate prediction potential of early tooth loss due to periodontitis. This model may have clinical and epidemiologic relevance towards the prediction of tooth loss burden.

Background: drugs provide a significant benefit; however, their use implies an intrinsic potential danger, with the possibility to cause unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3% / dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derivates from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). The totality of the ADR was classified as non-serious, and the 97.5% (n=80) was classified as mild and 2.5% as moderate (n=2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.

Objective: We tested a model of individual health literacy information sharing with family members, personal preventive behaviours and family well-being during the Coronavirus Disease 2019 (COVID-19) pandemic in Hong Kong. Methods: We analysed data of 1501 randomly selected Chinese adults from a cross-sectional survey in Hong Kong from 9 to 23 April, 2020. Individual health literacy about COVID-19 with the items extracted from the questionnaire in World Health Organization Risk Communication and Community Engagement (RCCE) Action Plan Guidance for COVID-19 preparedness and response, COVID-19 information sharing with family members, preventive behaviours against COVID-19 and family well-being were measured. Structural equation modelling analysis tested the proposed model. Findings: COVID-19 information sharing with family members partially mediated the association between individual health literacy and personal preventive behaviours. The direct effect of 0.24 was shown, and the indirect effect through COVID-19 information sharing with family members was small at 0.03 (Z = 3.66, p < 0.001). Family well-being was associated with personal preventive behaviours against COVID-19. The model was adjusted for sex, age, and socioeconomic status factors and had good fit with RMSEA = 0.04, CFI = 0.98, TLI = 0.96, and SRMR = 0.02. Conclusion: COVID-19 information sharing with family members was a partial mediator between individual health literacy and personal preventive behaviours against COVID-19. Strategies for enhancing health literacy and preventive measures against COVID-19 are needed to promote family well-being in the pandemic.

The aim of this study is to investigate the effect of two antiglaucoma procedures, namely trabeculectomy and Ex-PRESS mini-shunt insertion on the biomechanical properties of the cornea. This is a prospective study. Thirty patients (30 eyes) were included in the study. Nineteen eyes had an Ex-PRESS shunt inserted (Group 1) and 11 had trabeculectomy (Group 2). The examination time points for both groups were 1 to 3 weeks preoperatively and at month 1, 6 and 12 postoperatively. Corneal biomechanical properties [corneal hysteresis (CH) corneal resistance factor (CRF)] were measured with the Ocular Response Analyzer. In group 1, CH was significantly increased at 6 and 12 months compared to baseline values. Corneal hysteresis was also higher at 1 month postoperatively but this increase did not reach statistical significance. In group 2, the CH was significantly increased at all time points compared to the preoperative values. CRF decreased at all time points postoperatively compared to the preoperative values in both groups. The difference (preoperative values to postoperative values at all time points) of the CH and CRF between the two groups was also compared and no significant differences were detected between the two surgical techniques. Trabeculectomy and the EX-PRESS mini-shunt insertion alter significantly the corneal biomechanical properties as a result of the surgical trauma and the presence of the shunt in the corneal periphery. When compared between them they affect the corneal biomechanical properties in a similar way.

Plasma medicine is a new field focusing on biomedical and clinical applications of cold physical plasmas, including their anticancer effects. Cold plasmas can be applied directly or indirectly as plasma activated liquids (PAL). The effect of plasma activated cell growth medium (PAM) and plasma activated phosphate buffered saline (PAPBS) were tested using a plasma pen generating streamer corona discharge in ambient air, on different cancer cell lines (melanoma A375, glioblastoma LN229 and pancreatic cancer MiaPaCa-2) and normal cells (human dermal fibroblasts HDFa). The viability reduction and apoptosis induction were detected in all cancer cells after incubation in PAL. In melanoma cells we focused on detailed insights to the apoptotic pathways. The anticancer effects depend on the plasma treatment time or PAL concentration. The first 30 minutes of incubation in PAL were enough to start processes leading to the cell death. In fibroblasts, no apoptosis induction was observed, only PAPBS, activated for longer time, slightly decreased their viability. Anticancer effects of PAM and PAPBS on cancer cells showed selectivity compared to normal fibroblasts, depended on correctly chosen activation time and PAL concentration. This selectivity, supported by optimum ratio of hydrogen peroxide and nitrites in PAL, is very promising for potential clinical applications.

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregate in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aβ, and neurofibrillary tangles (NFTs) are used as pathological markers of AD, and eventually produces aggregation or misfolded protein. Importantly, it has been found that failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidences have been suggested that autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregate or misfolded proteins. Moreover, it has also been related that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through autophagy pathway which is known as aggrephagy. Therefore, the regulation of autophagy might be served as a useful approach to modulate the formation of aggresome associated in AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy.

Antibiotic resistance (ABR) is an emerging global threat to public health. Substantial evidence has indicated that community pharmacists (CPs) can play a critical role in managing the ever-increasing threat of antibiotic resistance. The study aimed to determine the knowledge, attitude, and practices of CPs (n=180) towards antibiotics and antibiotic resistance as well as to improve the rational use of antibiotics. Two phases of mixed methods (quantitative and qualitative) online study were conducted in Pakistan from August 2019 to March 2020 by using validated questionnaires and semi-structured interview data. Different statistical methods were used to tabulate the quantitative data whereas inductive thematic analysis was conducted to categorize themes from the qualitative data and draw conclusions. Approximately 64.4% were male (mean: 29-33 years old). Overall, CPs had good knowledge of and were familiar with superbugs and their roles in ABR (65.6%, Median=1, IQR=1) although they were poor in differentiating some antibiotic groups with their respective ABR patterns (31.1%, Median=1, IQR=1). Most CPs have a positive attitude towards antibiotics with most (90.0%) having identified ABR as a critical issue in public health (Median=1, IQR=0). Overall, CPs' practices towards antibiotics were reasonable where they tend to educate patients about the rational use of antibiotics (52.8%, Median=1, IQR=1). Two main themes (antibiotics and counseling of patients) were related to self-medication with while educational interventions are the sub-theme. ABR is multifactorial where the subthemes related to budget, time constraints incompetent staff, the absence of CPs, the lack of training, enforcement of laws and regulations are the need of the hour in Pakistan. Effective antibiotic stewardship programs, patient education, and awareness campaigns about antibiotics and ABR along with training of the CPs are important factors that have to be addressed in a timely manner.

The COVID-19 pandemic had profound negative effects on millions of couples affected by infertility and in need to resort to assisted reproductive technologies. There is no consensus over the optimal way and moment of screening triage-negative asymptomatic patients and staff. We present SARS-CoV-2 antibodies’ (IgM, IgG) seroprevalence in 516 triage-negative patients and 30 fertility care providers. The sampling for SARS-CoV-2 serological assays took place from the lockdown release throughout the second half of 2020 (17.05 - 01.12.2020). It revealed an increased seroprevalence of antibodies that closely followed the local epidemiology of COVID-19, with the highest rate of seropositivity coincident with the peak of the second wave. From 546 triage-negative individuals whose blood samples were assessed for SARS-CoV-2 antibodies, 6% yielded positive results. The overall seroconversion rate was 2.8% for IgG and 5.1% for IgM. In the group with positive IgM, we observed a negative predictive value for IgM of 98.36% (95% CI: 88.79 – 99.78%), which is clinically meaningful. Serological testing of triage-negative patients up to seven days prior to the actual fertility procedure might avoid the more expensive and not more sensitive molecular testing currently being used for patient screening in most fertility units.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature me-ta-analysis of APC splicing mutations. We found that 123 unique APC splice site mutations, in-cluding the one described here, have been reported in FAP patients, 69 of which have been char-acterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with 4 mutations causing skipping of exon 12 and/or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and 5 mutations leading to skipping of exon 5, 7, 8, and (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations considered in this study cluster with the AFAP phenotype and delineate a novel molecular mechanism of pathogenesis in FAP disease.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be largely explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

(1) Background: Overall survival of the patients with renal cell carcinoma (RCC) depends mostly on extra-renal extension, documented by the invasion of the pelvicalyceal system, or the perinephric/renal sinus fat or the renal vein/its segmental intraparenchymal branches. Staging may be challenging because of the high inter-observer variability. We have introduced a more accurate procedure to detect the extra-renal extension and, to possibly evaluate the impact of such more laborious approach, we have compared the RCC pathological staging obtained following both standard and modified procedures; (2) Methods: We selected 54 consecutive cases of RCC diagnosed 18 months before and 54 consecutive cases diagnosed 18 months after the introduction of the new method of sampling. Clinico-pathological characteristics have been statistically analyzed; (3) Results: Most of the features analyzed were non statistically significative, except the extra-renal invasion. More precisely, the occurrence of retrograde venous invasion was higher in the cases grossly approached with the more accurate method; (4) Conclusions: Extra-renal extension to intraparenchymal renal vein branches may be underestimated, leading to an inappropriate under-staging. Using more accurate staging procedures, to disclose the occurrence of intra-renal veins tumoral thrombosis, helps to better define the pathological stage, allowing patients to benefit of better fitting treatments.

Background: Post-operative delirium in elderly with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. The aim of this study is to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers.Methods: In this prospective study we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete Blood Count (CBC) and venous blood gas markers were obtained at the same time points.Results: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) (after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. Conclusion: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process. Oxygen administration may aggravate these pathways.

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with less than 50 cases occurring per year in the UK. These tumours are both chemotherapy and radiotherapy resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA-sequencing and methylation array analysis. A recurrent mutation within exon1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p. Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31 and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumorigenesis.

Transcranial direct current stimulation (tDCS) over the left Inferior Frontal Gyrus (IFG) was found to improve apraxia of speech (AOS) in post-stroke aphasia, speech fluency in adults who stutter, naming and spelling in primary progressive (PPA). This paper aims to determine whether tDCS over the left IFG coupled with AOS therapy improves speech fluency in patients with PPA more than sham. Eight patients with non-fluent PPA with AOS symptoms received either active or sham tDCS, along with speech therapy for 15 weekday sessions. Speech therapy consisted of repetition of increasing syllable-length words. Evaluations took place before, immediately after, and two months post-intervention. Words were segmented into vowels and consonants and the duration of each vowel and consonant was measured. Segmental duration was significantly shorter after tDCS than sham for both consonants and vowels. tDCS gains generalized to untrained words. The effects of tDCS sustained over two months post-treatment in trained words. Taken together, these results demonstrate that the tDCS over the left IFG facilitates speech production by reducing segmental duration. The results provide preliminary evidence that tDCS can maximize efficacy of speech therapy in non-fluent PPA with AOS.

Coronaviruses (CoVs) are a well-known group of viruses in veterinary medicine. We currently know four genera of Coronavirus, alfa, beta, gamma and delta. Wild, farmed and pet animals are infected with CoVs belonging to all four genera. Seven human respiratory coronaviruses have still been identified, four of which cause upper respiratory tract diseases, specifically, the common cold, and the last three that have emerged cause severe acute respiratory syndromes, SARS-CoV-1, MERS-CoV and SARS-CoV-2. In this review we briefly describe animal coronaviruses and what we actually know about SARS-CoV-2 infection in farm and domestic animals.

Neuroscience is a vast discipline that deals with the anatomy, biochemistry, molecular biology, physiology and pathophysiology of central and peripheral nerves. Advances made through basic, translational, and clinical research in the field of neuroscience have great potential for long-lasting and beneficial impacts on human health. The emerging field of biological therapy is intersecting with the disciplines of neuroscience and rheumatology, creating new horizons for interdisciplinary and applied research. Biological drugs, growth factors, neuropeptides and monoclonal antibodies are being developed and tested for the treatment of painful arthritic and rheumatic diseases. This concise communication focuses on the solutions provided by the fields of neuroscience and neuroimmunology for real-world clinical problems in the field of rheumatology, focusing on synovial joint pain and the emerging biological treatments that specifically target pathways implicated in osteoarthritis pain in peripheral nerves.

Non-alcoholic fatty liver disease (NAFLD) continues to rise and has become the most common cause of chronic liver disease among all ages and ethnicities. Metabolic disorders such as obesity and insulin resistance are closely associated with sarcopenia and NAFLD. Sarcopenic obesity is a clinical disorder characterized by the simultaneous loss of skeletal muscle and gain of adipose tissue. It is associated with worse outcomes in individuals with NAFLD. It is projected that NAFLD and sarcopenia will rise as the prevalence of obesity continues to increase at an unparallel rate. Recently, sarcopenia and sarcopenic obesity have gained considerable interest, but we still lack a well-defined definition and a management approach. Therefore, it is imperative to continue shining the light on this topic and better understand the underlying mechanism as well as treatment options. In this review article, we aimed to address the pathophysiology, impact, and outcomes of sarcopenic obesity on NAFLD.

Antioxidants have multiple protective roles in cells and can be used as a supplement to protect cells against cryopreservation-induced detrimental effects, including protecting sperm fertility quality. The antioxidant resveratrol (3,5,4-trihydroxy-trans-stilbene; RSV) has been shown to be a protective supplement for the cryopreservation of animal sperm, including human sperm. In this study, we assessed the effect of RSV supplementation on canine sperm cryopreservation. Semen was collected from four dogs and the effect of different concentrations of RSV (0, 100, 200, and 400 µM) on post-thaw quality of sperm was examined. After thawing, sperm motility was assessed using computer aided sperm analysis, and the structural integrity of the plasma membrane, acrosome, and chromatin were examined, as well as mitochondrial activity and gene expression were assessed. Dog sperm cryopreserved with 200 µM RSV showed significant improvement in motility and viability following thawing compared with that of the control group (p &lt; 0.05). Moreover, RSV-supplemented samples showed significantly higher numbers of sperm with an intact plasma membrane, active mitochondria, and structural integrity of acrosomes and chromatin than that of control samples (p &lt; 0.05). Furthermore, gene expression showed that RSV supplemented samples showed lower expression of pro-apoptotic (BAX) oxidative stress-related (ROMO1) and oxidative induced DNA damage repair (OGG1) whereas higher expression levels of anti‐apoptotic (BCL2) protamine-2 (PRM2), protamine-3 (PRM3) and sperm acrosome‐associated (SPACA3) genes than control. Our results suggest that RSV, at its optimum concentration, can be efficiently used as an alternative antioxidant in the cryopreservation of dog sperm.

Objective: We previously provided evidence to confirm that soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio, are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this study we examine the potential additive value of Inhibin-A, a hormone marker of the transforming growth factor family. Methods: We used a cohort of 125 pregnant women enrolled near delivery at clinics of the University Medical Center of Ljubljana, Slovenia. There were 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 iatrogenic preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 13 of PE, 12 of FGR, 22 of PE+FGR, and 6 of PTD. We recorded demographic characteristics and medical history and the levels of PlGF, sFlt-1 and Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations was estimated from areas under the curve (AUC) of Receiver Operating Characteristics (ROC) curves. We estimated accuracy by the continuous marker model and a cut-off model. Results: Combining Inhibin-A with PlGF or with the sFlt-1 / PlGF ratio showed a 10-20% increase in AUCs and 5-15% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR but not for FGR alone. The use of a cut-off model was adequate, although a bit higher accuracy was obtained from the continuous model. Highest correlation was found for PlGF with all three complications. Conclusion: Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by the angiogenic markers alone, bringing the results to a diagnostic level, thus assisting in directing clinical management. Inhibin-A had no added value for the accuracy of predicting FGR alone.

Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.

(1) Background: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study is aimed at showing the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. (2) Methods: 2173 Vacuum Assisted Breast Biopsies (VABB) documented as DCIS have been reviewed. Surgery has been performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion. (3) Results: We observed 2173 cases of DCIS: 408 classified as low grade; 1262 as intermediate grade; 503 as high grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was significantly lower (8.2%) when considering patients showing mammographically documented complete removal of the lesion. (4) Conclusion: The absence of mammographically documented residual lesion following VABB is associated to a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.

The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB) and fruit juices (FJ) is associated with the risk of different cardiometabolic diseases and probably with some tumors as well. We carried out a systematic review and meta-analysis of observational studies aimed at evaluating the association between sweet beverage intake and different types of cancer risk. Suitable papers published up to June 2020 were searched through PubMed, Web of Science and SCOPUS databases, using relevant keywords. Overall, 64 studies were identified for the systematic review, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest compared with the lowest sweet beverage intake categories. Random effects showed significant positive association between SSBs intake and breast (RR: 1.14, 95% CI: 1.01 – 1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10 – 1.27), also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01 – 1.05). Associations between SSBs and colorectal and pancreatic cancer risk, FJs and breast, colorectal and pancreatic cancer risk, ASBs and pancreatic cancer risk tended to be positive but did not reach the statistically significant threshold. This study supports the recommendation to limit the consumption of SSBs and FJs for cancer prevention and proposes to further investigate the potential harmful role of ASBs intake in cancer risk.

Aim: To establish, through molecular modelling, safe and clinically acceptable putative antagonists of E571K-mutated exportin-1 among the bioactive compounds in various parts of Juglans mandshurica. Methods: The bioactive compounds were subjected to compendium of druglikeness and lead-likeness filter workflows prior to docking of the resultant compounds into E571K exportin-1 active site using PyRx AutoDock vina to establish their binding affinity and interaction profile. The evolutionary algorithm of Osiris property explorer DataWarrior software as well as lead-likeness filter were employed for generation of novel non-promiscuous analogues of the lead compound with better putative selectivity and clinical acceptability as E571K Exportin-1 antagonists.Results: The findings of this study present taxifolin as the putatively effective and lead-like E571K Exportin-1 inhibitor with high potential of qualifying for clinical evaluation but is associated with high promiscuity tendency in high throughput screening. The evolutionary derivation of novel analogues of the compound, however, results in the generation of putatively non-promiscuous, non-toxic, and lead-like E571K Exportin-1 antagonists with high synthetic accessibility and clinical developability for evaluation in the strategy for treatment of drug-resistant KRAS-mutant lung adenocarcinoma condition.

Background. The aim of this study is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia. Methods. We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results. The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with latent vectors extracted from all symptoms, reflecting overall severity of psychosis (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion. Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe.

With the arrival of SARS-CoV-2 vaccines, a new stage of the pandemic commenced, with new challenges ahead. During the coming months, countries will be implementing their COVID-19 vaccination programs depending on their implementation of vaccine availability and its prescription on risk stratification. Although children will not benefit from active immunization programs, now, with the beginning of the era of the anti-COVID19 vaccines, the suffering of children can no longer be ethically tolerated or neglected. The time has come to provide specific lasting strategies for children living in the COVID-19 era. Here we propose a child-focused indirect COVID-19 vaccination strategy.For better or worse, children depend on their natural caregivers (adults) and the rest of society for their well-being and achieving their full potential. We believe that including in the priority categories also those adults in close contact with children could ensure a safety net of child protection.A child-focused vaccination strategy would allow the faster return to "normality" for children and their families. Such an approach would not only enable the reopening and continuity of essential services for children but also would allow adults to return to their routine economic/productive activities.

Objectives: A wealth of literature has established risk factors for social isolation among older people, however much of this research has focused on community-dwelling populations. Relatively little is known about how risk of social isolation is experienced among those living in long-term care (LTC) homes. We conducted a scoping review to identify possible risk factors for social isolation among older adults living in LTC homes. Methods: A systematic search of five online databases retrieved 1535 unique articles. Eight studies met the inclusion criteria. Results: Thematic analyses revealed that possible risk factors exist at three levels: individual (e.g., communication barriers), systems (e.g., location of LTC facility), and structural factors (e.g., discrimination). Discussion: Our review identified several risk factors for social isolation that have been previously documented in literature, in addition to several risks that may be unique to those living in LTC homes. Results highlight several scholarly and practical implications.

Gastric Cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third cause of cancer mortality worldwide. For advanced GC, a large number of novel drugs and combinations have been tested, but results are still disappointing and the disease incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression and ramucirumab, a monoclonal antibody binding to vascular endothelial growth factor-2 (VEGFR-2) is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. MicroRNAs (miRNAs) are a class of evolutionally conserved single-stranded noncoding RNAs playing an important role, via post-transcriptional regulation, in essentially all biologic processes such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. Notably, in our review, we focused on miRNAs involved in angiogenic pathways in GC. Moreover, we evaluated the possible prognostic and predictive role of angiogenesis-related miRNAs as novel biomarkers of GC.

Background. Pregnancy rates in women on dialysis have increased in the last decades, thus making it a topic of growing interest. The rarity of this event is predominantly due to fertility problems and to the high rates of pregnancy failure including stillbirth, fetal and neonatal deaths [1]. Methods. We conducted a narrative review of existent literature in order to analyse the major issues about pregnancy on dialysis to give the reader a full updated prospective about this topic which, even if not common, is becoming more and more frequent. Results. Even if recently acquired knowledge has improved diagnosis and treatment of dialysis pregnancies focusing on several aspects, pregnancy on dialysis remains a great challenge for obstetricians and should be managed by a multidisciplinary expertise team. Conclusion. Dialysis in pregnancy may be necessary for women previously affected by end stage renal disease (ESRD) becoming pregnant, or in case of acute renal injury presenting for the first time during gestation or, again in case of existent renal pathology worsening during pregnancy and requiring dialysis. Although some evidence suggests that more intensive dialysis regimens are correlated with better obstetric outcomes, the optimal therapeutic protocol still remains to be established.

The prevalence of cardiometabolic risk factors has increased in Slovakian adolescents as a result of serious lifestyle changes. This cross-sectional study aimed to assess the prevalence of insulin resistance (IR) and the associations with cardiometabolic and selected lifestyle risk factors in a sample of Slovak adolescents. In total, 2,629 adolescents (45.8% males) aged between 14 and 18 years were examined in the study. Anthropometric parameters, blood pressure, and resting heart rate were measured, fasting venous blood samples were analysed, and HOMA-IR was calculated. The mean HOMA-IR was 2.45±1.91 without a significant intersexual difference. IR (cut-off point for HOMA-IR=3.16) was detected in 18.6% of adolescents (19.8% males, 17.6% females). IR was strongly associated with overweight/obesity (especially central) and with almost all monitored cardiometabolic factors, except for TC and systolic BP in females. The multivariate model selected variables such as low level of physical fitness, insufficient physical activity, breakfast skipping, a small number of daily meals, frequent consumption of sweetened beverages, and low educational level of fathers as the significant risk factors of IR in adolescents. Recognizing the main lifestyle risk factors and early IR identification is important in terms of the performance of preventive strategies. Weight reduction, regular physical activity, and healthy eating habits can improve insulin sensitivity and decrease the incidence of metabolic syndrome, type 2 diabetes, and CVD in adulthood.

Titin is a giant protein that functions as a molecular spring in sarcomeres. Titin interplays the contraction of actin-containing thin filaments and myosin-containing thick filaments. The breakdown product of titin has been measurable in urine as urinary titin N-fragments. Urinary titin N-fragment was originally reported to be a useful biomarker in the diagnosis of muscle dystrophy. Recently, the urinary titin N-fragment has been increasingly gaining attention as a novel biomarker of muscle atrophy and intensive care unit-acquired weakness in critically ill patients, in whom titin loss is a possible pathophysiology. Furthermore, several studies reported that the urinary titin N-fragment also reflected muscle atrophy and weakness in patients with chronic illnesses. It may be used to predict the risk of post-intensive care syndrome or to monitor patients’ condition after hospital discharge for better nutritional and rehabilitation management. We provide several tips on the use of this promising biomarker in post-intensive care syndrome.

This study evaluated the impact of didactic videos and service user testimonial videos on mental illness stigma among medical students. Two randomized controlled trials were conducted in Nepal. Study 1 examined stigma reduction for depression. Study 2 examined depression and psychosis. Participants were Nepali medical students (Study 1:n=94, Study 2:¬n=213) randomized to three conditions: a didactic video based on the mental health Gap Action Programme (mhGAP), a service user video about living with mental illness, or a control condition with no videos. In Study 1, videos only addressed depression. In Study 2, videos addressed depression and psychosis. In Study 1, both didactic and service user videos reduced stigma compared to the control (F2,91=6.37, p=0.003). In Study 2 (depression and psychosis), there were no differences among the three arms (F2,210=2.07, p=0.13). When comparing Study 1 and 2, there was greater stigma reduction in the service user video arm with only depression versus service user videos with depression and psychosis (t(31)=-3.04, p=0.005). In summary, didactic and service user videos were associated with decreased stigma when content addressed only depression. However, no stigma reduction was seen when including depression and psychosis. This calls for different strategies based on types of mental illnesses. ClinicalTrials.gov identifier: NCT03231761

Migraine is one of the leading causes of disability worldwide [1,2]and patients with acute migraine frequently present to emergency departments (ED)[3]. The current literature suggests that ED treatment of migraine headache varies across institutions [4-7]. Considering this, we conducted a scoping review to summarize trends in medication prescribing patterns for acute migraine treatment in the ED setting. Trends were evaluated for factors influencing treatment choices, with particular attention placed on opioids and migraine specific therapy. This scoping review was based on the Arksey and O'Malley methodological framework[8]and included studies published between 1 January 2000 until 31 May 2020. 14 publications met the inclusion criteria. The most common classes of medication prescribed were often anti-emetics or Non-steroidal anti-inflammatory drugs (NSAID), but rates varied between studies. There was a concerning trend towards an underutilization of triptans and overutilization of opiates. The use of specific clinical goals of treatment (e.g. two-hour pain free freedom response) was also not evident. Additionally, 88% (n=8) of the 9 studies commenting on adherence to hospital or evidence-based guidelines stated that practices were non-adherent. Overall, the reviewed literature reveals treatment practices for acute migraine in the ED are heterogeneous and deviate from established international recommendations.

Objective: The Acute Cystitis Symptom Score (ACSS) was developed and validated as a self-reporting questionnaire for diagnosing and monitoring acute, uncomplicated cystitis (AC) in female patients. The study aims at the translation of the ACSS into Greek from original Russian as a source and American English as a new master version and at its linguistic validation. Material and Methods: Three independent professional native Greek translators, two of them experts in Russian and one in English, translated the ACSS from Russian and American English into Greek. The second group of three translators translated each of the three versions back into the original language to detect or correct any important discrepancies. These three Greek versions were then used for linguistic validation. Results: The English to Greek translation reflected more the spoken language, the two Russian to Greek translations more the written, formal language. A total of 60 randomly selected females and 30 healthcare professionals was asked about their preferences and to comment on each of the three translations. Considering all comments the scientific committee (SC) developed the Greek consensus version. For cognitive assessment additional 30 healthcare professionals and 30 females were asked to comment on the intelligibility of all items. Considering their comments the linguistically validated Greek study version was established by the SC. Conclusion: The linguistically validated Greek version of the ACSS can now be used for the clinical validation study.

The trace element selenium (Se) is taken up from the diet and becomes metabolized mainly by hepatocytes. Selenoprotein P (SELENOP) constitutes the liver-derived Se transporter. Biosynthesis of extracellular glutathione peroxidase (GPx3) in kidney depends on SELENOP-mediated Se supply. We hypothesized that Se status may serve as a useful prognostic marker for outcome in patients undergoing liver transplantation. Serum samples from patients were routinely collected before and after transplantation. Concentration of serum SELENOP and total Se as well as GPx3 activity were determined by standardized tests and related to survival, aetiology and pre-operative Child-Pugh and Model for End-Stage Liver Disease Scores. A total of 314 serum samples from 78 transplanted patients were available for analysis. The Se and SELENOP concentrations were on average below the reference ranges of healthy subjects. Patients with ethanol toxicity-dependent aetiology showed particularly low SELENOP and Se concentrations and GPx3 activity. Longitudinal analysis indicated declining Se concentrations in non-survivors. We conclude that severe liver disease necessitating organ replacement is characterized by a pronounced Se deficit before, during and after transplantation. A recovering Se status after surgery is associated with positive prognosis, and an adjuvant Se supplementation may thus support convalescence.

The neonatal Hub and Spoke (HandS) ECMO approach provides emergent ECMO implantation to support neonates in severe cardio-respiratory life-threatening conditions at secondary (Spoke) centers, and a safe transfer to the ECMO center (Hub). We report a retrospective review of 11 neonates fom January 2014 to January 2020, presenting with life-threatening conditions and treated by HandS ECMO team in Spoke hospitals. Protocols and checklists were arranged by a local group of ECMO experts and shared with all the hospitals located in North-Eastern Italy. At the emergent call, all patients were cared for at the Spoke hospitals, receiving maximal respiratory and cardiovascular support (including high frequency oscillatory ventilation, inhaled nitric oxide, and major inotropic intravenous infusion). All but 3 patients were affected by life-threatening meconium aspiration syndrome. Median duration of ECMO support and hospitalization were 4 days (range 2-32) and 30 days ( range 8-50), respectively. All but 2 patients with congenital diaphragmatic hernia, were weaned off ECMO and discharged home without complications. At a median follow up of 14.4 months (1.3-74.8), all survivors were alive and in good clinical conditions, without medications, and normal somatic growth. All but one had normal neuropsychological development. We conclude that HandS ECMO model for treating neonates in life-threatening conditions is effective and successful. A specialized multidisciplinary team and common organizational protocols shared between Hub and Spoke centers are the key-points for success. While excellent results occur with MAS (100% survival), treatment was not successful in CDH, in which other that HandS ECMO issues are implied. Lessons learned from our experience are presented and discussed in this article.

Capturing complexity is both a conceptual and a practical challenge in palliative care. The HexCom model has proved to be an instrument with strong reliability and valid for describing the needs and strengths of patients in home care. In order to explore whether it is also perceived to be helpful in enhancing coordinated and patient-centered care at a practical level, a methodological study was carried out to assess the face validity of the model. Particularly, a Delphi method involving a group of 15 experts representing the full spectrum of healthcare professionals involved in palliative care was carried out. The results show that there is a high level of agreement, with a Content Validity Index-Item greater than 0.92 both with regard to the complexity model and the HexCom-Red, HexCom-Basic and HexCom-Clin instruments, and higher than 0.85 regarding the HexCom-Figure and the HexCom-Patient instruments. This consensus confirms that the HexCom model and the different instruments that are derived from it are valued as useful tools for a broad range of healthcare professional in coordinately capturing of complexity in healthcare practice.

Background: Intrauterine device is a modern contraceptive method used in family planning process, it prevents conception (pregnancy) and it has duration of 12years. There some women of reproductive age who don’t use this method, which necessitates our concern to why they don’t use it. The aim of this study is to explore the knowledge and attitude toward utilization of IUCD as family planning method among women attending at Makambako RCH. Methods: A descriptive cross-sectional quantitative study was used to assess knowledge and attitude concerning use of intrauterine contraceptive device among 384 women of reproductive age. Random sampling was conducted in which every individual had an equal chance to be selected and structured self-administered questionnaire were used to collect data. Data was entered to Microsoft excel and then exported to SPSS version 20.0 for further analysis. Results: Findings of the study about 333 (86.7%) respondents had knowledge on IUD while 51 (13.3%) they lack knowledge on IUD and they agreed it helps to prevent unwanted pregnancies and they heard it from social media like radio and television, health care providers, friends and school. About 46 (12%) of the respondents had positive attitude and used IUD method of family planning, and they got influence of using IUD from health care providers, 82 (21.4%) got influence of using IUD from their partners and 27 (7.0%) influenced to use IUD due to the side effects of other family planning methods like Depo Provera and pills. 25 (5.7%) were not influenced by anyone to use IUD as family planning method. While 338 (88.0%) participants had negative attitude on IUD method and had never used IUD as family planning method. Conclusion: The findings show that IUD usage was found to be poor and majority of them they didn’t prefer it, despite of having less complications.

1) Background: Parents are increasingly fascinated by alternative weaning methods, such as ba-by-led or vegetarian weaning. However, international pediatric societies are still cautious to-wards alternative weaning methods, due to their significant risk of nutritional deficiencies. The aim of this study is to describe the attitude of Italian pediatricians towards unconventional weaning, with particular regard to vegetarian and baby-led. (2) Methods: A 20-question ques-tionnaire was sent to Italian pediatricians, from January to December 2019; (3) Results: Responses were received from 73/1000 (7.3%) pediatricians. The vast majority of surveyed pediatricians (78.1%) is familiar with baby-led and vegetarian weaning, but only 24.7% is in favor of their practice. A significant number of pediatricians (63.0%) received request from parents for an al-ternative weaning regimen. (4) Conclusions: The survey revealed a significant gap between pedi-atricians’ attitude and parental demand concerning unconventional weaning. This could signifi-cantly impair the alliance between parents and pediatricians with the risk to expose infants and children to severe nutritional deficiencies due to self-management by parents with poor surveil-lance from health professionals.

Abstract: 1) Background. This research examined feasibility, acceptability and outcomes of delivering a 6-week yoga-based meditation intervention to clinical teams of hospice professionals (HPs) at a large non-profit hospice organization. The intervention was designed to increase mind-body integration and combat burnout. The manuscript was written for different audiences including research scientists who study interoception, burnout, meditation, or yoga, designers of meditation interventions, and hospice organizations looking for ways to mitigate HP burnout. 2) Methods. The intervention was launched within clinical teams, beginning with a half hour online introduction to the program and exposure to the week 1 meditation at each team’s monthly all-staff meeting. Throughout the program, HPs could access the meditations on their own via their workplace computers, tablets, and smartphones. Online pre- and post-intervention surveys with 151 HPs assessed burnout using the Professional Fulfillment Index and mind-body integration using the Multidimensional Assessment of Interoceptive Awareness sub-scales. 3) Results. Half of HPs expressed a desire to continue to have access to the meditations after the 6-week program ended. Due to covid-19 work from home restrictions, three-fourth of HPs did a meditation at home, 29% in a car between patient visits (not while driving), and 23% at the office. Higher interoceptive awareness was significantly related to lower burnout, particularly lower work exhaustion. Meditation frequency was significantly related to higher interoceptive awareness but not to burnout. 4) Conclusions. Findings showed that yoga-based meditation intervention was feasible and acceptable and associated with higher interoceptive awareness. The results point to a role for interoceptive awareness in reducing the risk for burnout.

The COVID-19 pandemic has raised questions about the possible cross immunity resulting from common vaccination programs and SARS-CoV-2 infection. Therefore, the Spanish Obstetric Emergency group performed a multicenter prospective study on the vaccination status of Influenza and Tdap (diphtheria, tetanus and pertussis vaccine boost administered in adulthood) in consecutive cases of SARS-CoV-2 infection in a pregnancy cohort, in order to assess its possible association with the clinical presentation and severity of symptoms of SARS-CoV-2 infection, as well as to determine the factors that may affect vaccination adherence. 1,150 SARS-CoV-2 positive pregnant women from 78 Spanish hospitals were analyzed: 183 had not received either vaccine, 23 had been vaccinated for Influenza only, 529 for Tdap only and 415 received both vaccines. No association was observed between the vaccination status and the clinical presentation of SARS-CoV-2 infection and/or the severity of symptoms. However, a lower adherence to the administration of both vaccines was observed in the Latin-American subgroup. Based on the results above, we reinforce the importance of maternal vaccination programs in the actual pandemic. Health education campaigns should be specially targeted to groups less likely to participate in these programs, as well as for a future SARS-CoV-2 vaccination campaign.

Background: Rituximab is a monoclonal antibody widely used in the treatment of inflammatory and autoimmune disorders. Despite reports of its effectiveness in the treatment of demyelinating diseases of central nervous system (DDCNS), it is not yet approved for use in these disorders. The aim of this study was to investigate the effectiveness and safety of low dose rituximab in three different subgroups of DDCNS including relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS) and neuromyelitis-optica-spectrum disorders (NMOSD).Methods: In a prospective cohort study, we monitored expanded-disability-status-scale (EDSS), relapses (new attacks) and serum-IgG levels to assess effectiveness and drug-adverse-events for safety in patients with RRMS, SPMS and NMOSD. These patients were candidates to receive rituximab according to our common practice protocol. We switched patients to rituximab if there was poor response to first line therapies. We follow a low dose protocol in our center (500 mg twice, two weeks apart, repeating every six months) and these patients treated in a 4-year period were assessed retrospectively for evaluation of our protocol’s safety and effectiveness. Results: 99 patients (42 RRMS, 43 SPMS and 14 NMOSD) received rituximab for a range of 12 to 40 months period. New attacks occurred in 8 RRMS (19%), 10 SPMS (23%) and 1 NMOSD (7%) patients. EDSS decreased in RRMS and NMOSD cases. Serum-IgG levels decremented in SPMS and NMOSD patients. Drug-adverse-events happened in two cases.Conclusion: In this study, low dose rituximab showed substantial effectiveness in preventing disease progression with a considerably good safety profile.

Left ventricular noncompaction (LVNC) and hypertrophic cardiomyopathy (HCM) commonly occur as separate disorders with distinct clinical and pathoanatomical features. However, these cardiomyopathies may have a similar genetic origin with mutations encoding sarcomeric proteins. The described case demonstrates an example, in which phenotypic expression of both diseases occurs in the same patient.

Epidemiological studies have shown a strong association between high body mass index (BMI) and papillary thyroid cancer (PTC). We assessed the clinical and histopathological features of PTC in patients with a higher BMI and compared them to analogous parameters in PTC patients with a normal BMI. We retrospectively analyzed 5,021 medical records of patients admitted and surgically treated for thyroid tumors in one center between 2008 and 2018. Finally, we extracted data from 523 adult patients with PTC and stratified patients into two groups according to BMI: Group 1 with BMI < 25 kg/m² and Group 2 with BMI ≥25 kg/m². Data stratification was performed to estimate the association of overweight and obesity with clinical and histopathological features of PTC in both univariate and multivariate binary logistic regression analyses. Overall, compared to patients with a normal BMI, overweight and obese patients had a greater risk of minimal extrathyroidal extension (minimal ETE), multifocality and bilaterality of PTC (p<0.001 for all). Analysis did not show that BMI was significantly associated with more advanced tumor-node-metastasis (TNM) stage (p=0.894). Obesity and overweight were significantly associated with higher aggressiveness of PTC. When considering various management options for PTC patients, these findings regarding overweight and obesity should be taken into consideration during the decision-making process.

A prominent feature of stress-tolerant microalgae is their versatile metabolism allowing then to synthesize a broad spectrum of molecules with beneficial effects on many aspects of human body functioning. This is in line with the current understanding that many stress-induced deleterious processes in the human body and in photosynthetic cell are mediated by the same mechanisms such as free-radical attacks and lipid peroxidation. These related risks are kept at bay by optical screening of harmful UV, enzymatic ROS elimination systems, and potent low-molecular antioxidants. Microalgae synthesize a broad spectrum of compounds exerting antioxidant and/or UV-absorbing properties. In microalgae, they increase stress-resilience of these organisms. In human body, they exhibit photoprotective, antiaging, and sunscreen activities. Therefore, these algal metabolites were recognized as promising ingredients for innovative cosmetics and cosmeceutical formulations. Ever increasing effort is being invested into the search for new natural biologically active substances from microalgae. This trend is also fueled by the growing demand for natural raw materials for food, pharmaceuticals and cosmetology associated with the global transition to a "greener" lifestyle. Here, we review the currently accumulated knowledge about the main groups of cosmeceutical compounds from microalgae.

Achievement of solid fusion of the lumbosacral junction (L5-S1 level) is an important factor in adult spinal deformity (ASD) surgery. The purpose of this study is to explore the effectiveness and feasibility of injectable rhBMP-2 (a combination of Eschericia coli-derived rhBMP-2 and hydrogel type β-TCP carrier; NOVOSIS Inject) as a bone substitute for the fusion of lumbosacral junction. 20 patients (average age 69.1 years) diagnosed with ASD with sagittal imbalance who underwent surgical treatment including anterior lumbar interbody fusion (ALIF) in the L5-S1 level were evaluated. Injectable rhBMP-2 was applied in L5-S1 ALIF and followed-up for 1-year. Solid fusion rates and changes of clinical outcomes (Oswestry Disability Index [ODI], Visual Analog Scale [VAS] of back and leg) were measured and analyzed at 6 and 12 months after surgery. All postoperative adverse events were evaluated about the association with injectable rhBMP-2. Fusion rates were 68.4% and 100% at 6 and 12 months after surgery. Compared to baseline, ODI were improved to 45.8% and 63.7%, VAS(back) were improved to 69.2% and 72.8%, and VAS(leg) were improved to 49.2% and 64.8% at 6 and 12 months after surgery (p&lt;0.001, respectively). There were no adverse events associated with injectable rhBMP-2. Thus, injectable rhBMP-2 may be a suitable choice of a bone graft substitute when achieving solid interbody fusion in the lumbosacral junction.

This study aims to establish whether the use of biomaterials, particularly polydimethylsiloxane (PDMS), for surgical reconstruction of the esophagus with templates, Montgomery salivary tube, after radical oncology surgery for malignant neoplasia is an optimal choice for patients’ safety and for optimal function preservation and organ rehabilitation. Methods: Structural analysis by Raman spectrometry and biomechanical properties with dynamic mechanical analysis are performed for fatigue strength and toughness, essential factors in durability of a prosthesis in the reconstruction practice of the esophagus. Nanocomposites with silicone elastomers and nanoparticles used in implantable devices and in the reconstruction surgery are facing risks of infection and fatigue strength when required to perform a mechanical effort for long periods of time. Results: This report takes into account the effect of silver (Ag) nanoparticles on the fatigue strength using polydimethylsiloxane (PDMS) matrix, representative for silicon elastomers used in implantable devices. PDMS with 5% (wt) Ag nanoparticles of 100-150 nm during mechanical fatigue testing at shear strength loses elasticity properties after 400 loading-unloading cycles and up to 15% shear strain. The fatigue strength, toughness, maximum shear strength are the key issues in designing Montgomery salivary tube with appropriate biomechanical behavior for each patient. Conclusions: Prosthesis design needs to indulge both clinical outcome as well as design methods and research in the field of biomaterials.

Adrenal crisis (AC) is an unexpected and possibly lethal situation of stressful interventions in patients with Addison’s disease (AD). Despite being rare in dentistry, it is to be noted that evidence indicates that 5-8% of patients with AD necessitate emergency glucocorticoid administration to treat AC annually. For that, dentists must be aware of this condition and be prepared when the clinical signs and symptoms occur.

Background: Interleukin (IL)-33 is a member of interleukin (IL)-1 family of cytokines which has been linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has direct effect on human gastric epithelial cells (GES-1) and on human gastric adenocarcinoma cell line (AGS), assessing its role in regulation of cell proliferation and cell cycle, apoptosis and necrosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Methods: cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assay, we also evaluated apoptosis and necrosis by Caspase 3/8 Activity assay and Propidium Iodine/Annexin V assays. Cell cycle were analyzed by means of Propidium Iodine assay and gene expression regulation was assessed by RT-PCR Profiling. Results: we found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell line, while it can stimulate proliferation and reduce apoptosis in normal epithelial cell line. These effects are also confirmed by the analysis of cell cycle gene expression which showed a reduced expression of proproliferative genes in AGS cells, in particular genes involved in G0/G1 and G2/M checkpoint. These results are confirmed by the gene expression analysis on surgical and bioptic specimens. Conclusions: the aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell type-dependent fashion.

Whether resurfacing or not resurfacing the patella during total knee arthroplasty (TKA) still is a challenge to orthopedic surgeons. A significant reason for this controversy is the far from perfect outcomes of both techniques, resulting from inadequate knowledge of normal patellar dimensions in a diseased one. The primary purpose of the current study is to find the pre-diseased patellar dimensions and the ethnic differences in patellar dimensions. We measured the patella's dimensions on 927 normal young adult knee MRIs from seven different ethnicities. Besides comparing the dimensions between sexes, ages, and sides, we analyzed the differences among ethnic groups. The average thickness was 25.12±2.33 mm; the average width was 44.57±4.32 mm, the average articular surface length was 32.69±3.75 mm, with significant gender, age, and ethnic differences. There were also significant differences in dimensions among ethnic groups, except for between the Indians and Far Eastern Asians and between the Arabs and North Africans. We could also find a robust mathematical relationship between the patella's width, length, and thickness. The ethnic differences in patellar dimensions found in this study can help optimize surgical technique and implant designs for patellar resurfacing. The mathematical equation will help the surgeons find the normal, pre-diseased patella thickness to prevent over-or under-stuffing during the patellar resurfacing.

The oncogenic potential of high-risk HPVs is focused on producing the E6 and E7 oncoproteins responsible for disrupting the control of the cell cycle. Epidemiological studies propose the presence of the N29S and H51N variants of the HPV16 E7 protein as a significant association with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains unknown. Analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose for the first time a 3D structure of the E7 reference protein and two of its variants (N29S and H51N) and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

We investigated effects of molecular hydrogen (H2) supplementation on acid-base status, pulmonary gas exchange responses, and local muscle oxygenation during incremental exercise. Eighteen healthy, trained subjects in a randomized, double-blind, crossover design received H2-rich calcium powder (HCP) (1500 mg/day, containing 2.544 µg/day of H2) or H2-depleted placebo (1500 mg/day) for 3 consecutive days. They performed cycling incremental exercise starting at 20-watts work rate, increasing by 20 watts/2 min until exhaustion. Breath-by-breath pulmonary ventilation (VE) and CO2 output (VCO2) were measured and muscle deoxygenation (deoxy[Hb + Mb]) was determined via time-resolved-NIRS in the vastus lateralis (VL) and rectus femoris (RF). Blood gases' pH, lactate, and HCO3− concentrations were measured at rest and 120-, 200-, and 240-watt work rates. At rest, the HCP group had significantly lower VE, VCO2, and higher HCO3−, PCO2 versus placebo. During exercise, a significant pH decrease and greater HCO3− continued until 240-watts work rate in HCP. The VE was significantly lower in HCP versus placebo, but HCP did not affect the gas exchange status of VCO2 or oxygen uptake (VO2). HCP increased absolute values of deoxy[Hb + Mb] at the RF but not VL. Thus, HCP-induced hypoventilation would lead to lower pH and secondarily impaired balance between O2 delivery and utilization in the local RF during exercise, suggesting that HCP supplementation, which increases the at-rest antioxidant potential, affects the lower ventilation and pH status during incremental exercise. HPC induced a significantly lower O2 delivery/utilization ratio in the RF but not the VL, which may be because these regions possess inherently different vascular/metabolic control properties, perhaps related to fiber-type composition.

Background: Physical activity is recommended to mitigate the incidence of obesity, but delivery of community wide initiatives is cumbersome. The challenges met by such programs are magnified when implementation transpires in the remote villages of Alaska. To overcome the difficulty of this challenge in the Arctic, the Skiku/AK Nordic cross-country skiing program was developed. The objective of this study was to evaluate whether access to Skiku/AK Nordic program would promote physical activity levels that met the daily recommendations for physical activity in Alaska Native children. Methods: Eight children (4 females and 4 males; 10±2 years/age) were recruited from Kaktovik, Alaska for participation in this study. Expert coaches and staff provided one week of cross-country ski instruction and access to ski equipment. Physical activity was monitored using ActiGraph GT3X+ accelerometers. Data collected from the devices was then downloaded and analyzed using ActiLife software. Results: The participants expended ~586 calories/day devoted to physical activity. Light and moderate physical activity was 68±38 minutes/day and 447±248 minutes/day, respectively. Conclusions: Delivery of the Skiku/AK Nordic program promoted favorable levels of physical activity in Alaska Native children. Further research is needed to assess the longitudinal and seasonal effectiveness of the Skiku/AK Nordic program.

Loneliness is a frequent negative feeling among older people. A programme aimed at alleviating loneliness among older people by promoting social capital, i.e. social support and participation, was conducted in primary health care centres in Spain. We aimed to explore participants’ experiences of loneliness and social participation before the programme, perceived programme effects and contextual influences. A descriptive-interpretative qualitative design was used. 41 persons were included comprising older people, health and social care professionals, and volunteers. Data were collected through three focus groups, 36 semi-structured interviews and participant-observation of the intervention. A thematic content analysis was applied. Older persons with diverse profiles of loneliness and participation decreased their loneliness, increased their knowledge and participation in local community assets, and developed companionship, a sense of belonging, peer support and friendship. Their mental wellbeing increased and participants could deal better with health or family problems. An empowerment process was observed. However, loneliness persisted among some widowed participants and health and social vulnerabilities hampered some impacts. Conflicts and exclusion were occasional unintended effects. The promotion of social capital in ageing to alleviate loneliness involves complex processes interrelated with health and socio-economic factors. Future programmes should be adapted to local contexts and participants’ characteristics.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can also improve skeletal muscle performance both in human and mice. We here showed that dexamethasone induced atrophy, evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression , and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLRP3, Caspase-1 and GSDMD. Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine administration ameliorated dexamethasone-induced muscle atrophy both in vivo and in vitro. Moreover, trimetazidine improved exercise tolerance, as evidenced by increased running distance and running time, as well as increased skeletal muscle mass in dexamethasone-treated mice. Mechanically, trimetazidine could reverse dexamethasone-induced activation of pyroptosis both in C2C12 myotubes and in mice. Taken together, our present study demonstrated that NLRP3/GSDMD pathway-mediated pyroptosis was involved in dexamethasone-induced skeletal muscle atrophy. Trimetazidine could partially alleviate dexamethasone-induced skeletal muscle atrophy, and increase the diameter of C2C12 myotubes via inhibiting pyroptosis. Thus, trimetazidine might be a potential therapeutic compound for the prevention of muscle atrophy in glucocorticoid-treated patients.

Abstract: Viremia in coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is often only discussed in passing and there are very few references detailing its structural mechanisms. In addition to viremia in the classic closed cardiovascular system, the lymphatic system is discussed in relation to a possible “lympho-viremia”. The cells that comprise each of these separate but interacting systems will be examined and include endothelial cells, erythrocytes, leukocytes (monocytes/monocyte-derived macrophages and resident tissue macrophages) (lymphocytes) (neutrophils) and thrombocytes -platelets. The SARS-CoV-2 virus has been identified in multiple extrapulmonary target organs at autopsy in those with severe COVID-19 requiring intensive care. Vulnerable COVID-19 patients may suffer from multiple storms including viral/virion storm, redox storm, cytokine storm and thrombo-embolic storm. Therefore, it is important that the possible mechanisms of viremia be explored in greater detail and how these mechanisms might affect intravascular blood components, extracellular tissue interstitium and organ structural remodeling and function. While the co-morbidity of T2DM does not increase the risk of acquiring COVID-19, it is commonly accepted that T2DM increases the risk for COVID-19 admissions to hospitals, assisted ventilation, morbidity and mortality. Importantly, the co-existence of T2DM and COVID-19 may have synergistic detrimental outcomes.

The knowledge of what separates us genetically from our less-evolved relatives is crucial for gaining new biomedical insights about the human-chimpanzee relatedness for the use of appropriate stand-in towards the development of new treatments and diagnostic aids for various ailments. Although the genomes of humans and chimpanzees share 99% similarity, significant differences exist between the two species in their non-coding intronic regions. However, no work has been carried out in the aspects of target prediction concerning the ‘predicted homology’ in their microRNA sequences. Non-coding miRNAs which are post-transcriptional regulators of development, differentiation, growth, and metabolism, harboring the intronic regions may be crucial for expanding the horizons of our understanding. In this study, we proposed to perform the target prediction for the human-chimp miRNA homologs in the PHEX gene of the human X chromosome using various computational tools and databases. We identified a total of 1296 human miRNAs, 46, 957 gene targets, and 30, 563 targets of human and homologous chimp miRNAs respectively. Furthermore, we analysed gene interacting networks to identify the top interacting targets in both the species. Finally, we interpreted the biological importance of top-interacting miRNAs and their targets. The results demonstrated varying levels of multiplicity and cooperativity between the predicted miRNAs and target genes in the two genera. Such miRNAs may be responsible for the dysregulation of gene expression in several signaling pathways.

Gut microbiota and its metabolites like short chain fatty acids (SCFAs) are linked with pathology of Alzheimer’s disease (AD)- a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from SCFAs produced by microbiota in the gut. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists, using in-silico library of more than 144,000 natural compounds, and 15 compounds were selected based on binding with FFAR2 agonist sites. Further, cell culture toxicity and FFAR2 stimulatory experiments demonstrated that Fenchol (a natural compound commonly present in basil) was potent FFAR2 agonist in neuronal cells. Interestingly, we also demonstrated that Fenchol protects Aβ-stimulated neurodegeneration in FFAR2 dependent manner. In addition, Fenchol reduced AD like phenotypes such as Aβ-accumulation and, learning and memory behaviors in Caenorhabditis (C.) elegans. Fenchol increased Aβ-clearance by increasing proteasome/lysosome activity and reduced senescence in neuronal cells. These results demonstrated that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while activating it by Fenchol as a natural agonist reverse it by promoting Aβ-clearance and reducing cellular senescence; thus stimulation of FFAR2 signaling can be a therapeutic approach to prevent/ treat AD.

All infections are potentially curable as long as the etiological agents are susceptible to antimicrobials. The increased rate at which antimicrobials are becoming ineffective is a global health risk of increasing concern that threatens withdrawal of beneficial antimicrobials for disease control. Increased demand for food of animal origin, in particular eggs, meat and milk has led to intensification and commercial production systems where excessive use and misuse of antimicrobials may prevail. Antimicrobials, handled and used by farmers and animal attendants with no formal education may predispose to incorrect dosages, misuse, incorrect applications and non-adherence to withdrawal periods. A multimethod approach (desk review, field study and interviews) was used. Relevant establishments were also visited. High levels of resistance to penicillin G, chloramphenicol, streptomycin and oxytetracycline have been reported especially for Actinobacter pyogenes, Staphylococcus hyicus, Staphylococcus intermedius and Staphylococcus aureus from dairy cattle with mastitis and in humans. Similar trends were found in poultry where eggs and meat are contaminated with Escherichia coli strains resistant to amoxicillin + clavulanate, sulphamethoxazole and neomycin. An increasing trend of emerging multidrug resistant E. coli, Klebsiella pneumoniae, Staphylococcus aureus, and Salmonella was also found in food animals. An in-crease in methicillin resistant Staphlococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL) in the livestock sector in Tanzania have been reported. Specific antimicrobials resistant to were ampicillin, augmentin, gentamicin, cotrimoxazole, tetracycline, amoxicillin, ampicillin, gentamicin, streptomycin, erythromycin, tetracycline, ciprofloxacin, nalidixic acid, azithromycin, chloramphenicol, tylosin, erythromycin, cefuroxime, norfloxacin and ciprofloxacin. An in-creased usage of antimicrobials for prophylaxis, anaphylaxis and therapeutics against pathogens and for growth promotion in livestock, aquaculture and crops production were observed. One Health strategic approach is advocated to combat AMR in the food and agriculture sectors in Tanzania. Practical recommendations include a) legislation review and implementation, b) AMU, AMR and AR awareness and advocacy among stakeholders along the value chain, c) strengthening of surveillance and monitoring programs for AMU, AMR and AR, d) enhance development and use of rapid and innovative diagnostic tests and promotion biosecurity principles and e) good husbandry practices. The utilization of this information to improve public health policies and reduce the burden of AMR will be beneficial.

We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved more than a 2-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, BCS class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer polyvinylpyrrolidone–vinyl acetate (PVP–VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and DLS. The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a 4-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal0 tract (GIT), including Crohn’s disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e. g. vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α, 25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g. butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD /VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.

Conformal radiotherapy is a primary treatment in head and neck cancer, which putative adverse effects depend on relatively low doses of radiation delivered to increased volumes of normal tissues. Systemic effects of such treatment include radiation-induced changes in serum lipid profile, yet dose- and volume-dependence of these changes remain to be established. Here we analyzed levels of choline-containing phospholipids in serum samples collected consecutively during the radiotherapy used as the only treatment modality. The LC-MS approach applied in the study enabled the detection and quantitation of 151 phospholipids, including (lyso)phosphatidylcholines and sphingomyelins. No statistically significant differences were found in the pre-treatment samples from patients with different location and stage of cancer. To compensate for potential differences between schemes of radiotherapy the biologically effective doses were calculated and used in the search of correlations with specific lipid levels. We found that the levels of several phospholipids depended on the maximum dose delivered to the gross tumor volume and total radiation energy absorbed by the patient’s body. Increased doses correlated with increased levels of sphingomyelins and reduced levels of phosphatidylcholines. Noteworthy, serum phospholipid levels were associated mainly with volumes of normal tissues irradiated with relatively low doses (i.e., total accumulated dose 20 Gy), which indicated the importance of such effects on the systemic response of the patient’s organism to IMRT.

(1) Background: Obstetric work requires good communication, which can be trained in interventions targeting health care providers and pregnant women/ patients. This systematic review aims to aggregate the current state of research on communication interventions in obstetrics. (2) Methods: Using the PICOS scheme, studies published in peer-reviewed journals in English or German between 2000 and 2020 were searched. Out of 7,018 results, 71 studies were included in this synthesis and evaluated using the Oxford Level of Evidence Scale. (3) Results: 63 studies, including a communication component, revealed a positive effect on different proximal outcomes (i.e., communication skills). Three studies evaluating the effect of communication training on distal performance indicators (i.e., patient safety) proved to be beneficial to some extent. Most studies included different groups at the same time; those addressing health care providers were more common than those with students (61 vs. 12). Expectant mothers were targeted only in 9 studies. Overall, the evidence level of studies was low (only 11 RCTs), with 24 studies evidence level of I-II, 35 of III, and 10 of IV. (4) Conclusions: Communication training should be applied more often to improve communication of staff, students, and pregnant women, and thereby improve patient safety.

Objectives: Isolated mild neutropenia is a common clinical problem. The current study aims to validate our previous findings regarding the high prevalence of isolated neutropenia in Southern and Southwestern Saudi Arabia and explore the effect of altitude or regional differences. Methods: In this retrospective cross-sectional study, laboratory results of a commercial laboratory were screened over a period of 5 years (2016–2020) in seven different cities in South and southwestern Saudi Arabia. Participants’ laboratory investigations were reviewed and excluded for any ab-normal complete blood count, renal profile, liver profile, lipid profile, thyroid function test, fasting blood glucose, or HbA1c findings. Descriptive analysis and 95th percentile range were calculated using standard statistical methods. Results: A total of 91,880 complete blood count results were included in the final analysis. isolated neutropenia is common laboratory finding, with a prevalence ranging from 11-23%. The 2.5th percentile of the neutrophil count was lower than 1.5×109/L in all seven cities. Conclusions: Mild to moderate neutropenia is common in Southern and Southwestern Saudi Arabia. Benign ethnic neutropenia (BEN) may explain this high prevalence. Since BEN has no clinical significance, the reference range for normal neutrophil counts needs to be adjusted to reflect the effect of BEN.

Peri-implant diseases are defined as pathological inflammatory reactions in the tissue surrounding the osseointegrated implants. They are classified into two categories: mucositis - defined as peri-implant soft tissue inflammation and peri-implantitis - bone loss in the peri-implant region. A clinical case of a 61-years-old woman with an implant in the 46 anatomical position and a 5-year follow-up is presented. A probe depth of 5mm and a bone defect length of 35% was observed. The Implacure® Protocol was applied, with the main objective of eliminating the biofilm present on the exposed implant surface. There are multiple approaches to treat peri-implant diseases. While non-surgical treatment is essential for mucositis control, the treatment of peri-implantitis surgical treatment should be considered. Regenerative bone reconstruction promotes bone repair in the defect area and reduces bleeding during probing. To achieve that, autologous fibrin combined with Cerasorb M® was used. The proposed approach in the exposed clinical case involves the application of Implacure® Protocol, whose combination of the physical decontamination technique, together with the use of chlorhexidine and orthophosphoric acid, added with the combination Piperacillin + Tazobactam together with hyaluronic acid, provide a base that allows to regenerate bone using platelet-rich fibrin with Cerasorb M® and increase the survival time of the implant.

We report the treatment of a 21-year-old female Covid-19 patient by a novel combination of minocycline and a guanosine-restricted diet. Minocycline is an antibiotic with well documented broad spectrum anti-viral effects, including evidence of activity against SARS-CoV-2. Deprivation of guanosine has been documented as an effective anti-viral modality in vitro and in animal models, and specific in vitro activity against CoV-SARS-2 has been reported. The patient's symptoms resolved rapidly.

: Plant-derived terpenes have aroused considerable interest as chemotherapeutic agents for a variety of diseases. This study aimed at the isolation and purification of the scarce terpenes psiadin, plectranthone and saudinolide from their respective plants, followed by the determination of antiproliferative activity, against hepatic cancer cell lines (HepG2, Hep3B), and the potential molecular mechanisms. Time- and dose-dependent cytotoxicity, evaluated using MTT and colony-forming assays, were exhibited by psiadin and plectranthone against the cancer cells. Flow cytometry showed that these two terpenes blocked cell cycle progression and induced mitochondrial-mediated apoptosis, particularly through increased cytochrome c and disruption of mitochondrial membrane potential. Additionally, they initiated the generation of reactive oxygen species as well as inhibiting NF-B. Psiadin lowered several essential cyclins and cyclin-dependent kinases and reduced RB activation. It was concluded that psiadin, in particular, has a significant therapeutic potential with the biggest advantage of differentiating between cancer and normal cells which is acutely lacking in current cytotoxic drugs. Its precise mode of action needs further investigation but appears predominantly to cause cell cycle arrest by interfering with cyclin production. It will be important to determine, in future studies, whether these terpenes will similarly inhibit other cancer cell lines and retain its activity against tumors in vivo.

Researchers have developed and used several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids. Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anticancer drugs have been done in 2D culture systems, where-as 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aim to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyro-sine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter tumoroid growth of metastatic colorectal cancer (mCRC). To establish a liquid-based 3D multiplexing reporter assay system, LuM1 (a murine mCRC cell line) was stably transfected with the Mmp9 promoter-driven ZsGreen reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate (NCP), a 3D culture device. The larger tumoroids were not sensitive to Cisplatin and ex-pressed ABCG2 (a marker of cancer stem cells, a.k.a. a drug efflux transporter), whereas smaller cell-aggregates were more sensitive to Cisplatin. Both Imatinib and Cisplatin significantly in-creased tumoroid growth (larger than 300 μm2) and Mmp9 promoter activity and were not cytotoxic to the mCRC tumoroids. On the other hand, 5-FU was cytotoxic to the tumoroids and significantly inhibited tumoroid growth, although not completely. Thus, platinum resistance and imatinib resistance in mCRC were modeled using the liquid-based 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance.

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are reported. The future directions of the development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.