Editor’s Choice Articles

Background and objectives: The use of antagonistic probiotic microorganisms and their byproducts represents a promising approach for the treatment of viral diseases. In the current work, the effect of exopolysaccharides (EPSs) produced by lactic acid bacteria from different genera on the structural and functional characteristics of cells and the development of adenoviral infection in vitro was studied. Materials and Methods: Cytotoxicity of six EPSs of lactic acid bacteria of the genera Lactobacillus, Leuconostoc and Pediococcus was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the EPSs on the infectivity of human adenovirus type 5 (HAdV-5) and on the cell cycle under a condition of adenovirus infection was studied using plaque reduction assay and flow cytometric analysis, respectively. Results: It was shown that exopolysaccharides were non-toxic to Madin-Darby bovine kidney cells (MDBK) as they reduced their viability by 3–17%. A change in the distribution of the cell cycle phases in the non-infected cell population treated with EPSs was observed. The analysis demonstrated an increase in the number of cells in the S phase by 47% when using EPSs 15a and a decrease in the number of cells in the G1 phase by 20–27% when treated with the EPSs 15a, 33a, and 19s. The use of EPSs did not led to the normalization of the life cycle of HAdV-5 infected cells to the level of non-infected cells. The EPSs showed low virucidal activity and reduced the HAdV-5 infectivity to 85%. Among the studied exopolysaccharides, anti-adenovirus activity was found for EPS 26a that is produced by Lactobacillus spp. strain. The treatment of cells with the EPS following virus adsorption completely (100%) suppressed the formation and release of HAdV-5 infectious. Conclusions: EPS 26a possessed distinct anti-HAdV-5 activity and the obtained data demonstrate the potential of using exopolysaccharides as anti-adenoviral agents. Full article

Background and objectives: Despite the serious concerns of patients about the role of food in triggering or ameliorating their intestinal disease, there are few studies dealing with patients’ beliefs and practices regarding diet in inflammatory bowel disease (IBD). The aim of this study was to investigate how the disease affected the dietary habits of patients with IBD, and to assess if patients’ food restrictions were responsible for low bone mineralization. Materials and Methods: For this study, 90 consecutive patients referred for IBD were interviewed regarding their dietary habits. Demographic features and clinical characteristics potentially associated with the dietary habits were collected. A validated and self-administered survey questionnaire dealing with dietary habits and patients’ beliefs and perceptions regarding food was analyzed. Multivariate logistic regression analysis was performed in order to identify risk factors for dietary restrictions among participants and to evaluate the relationship between dietary restrictions and low bone mineral density (BMD). Results: Among the 63 (70%) patients who claimed a self-prescribed dietary restriction, 84% avoided dairy products. Significant risk factors (adjusted odds ratio (OR), 95% confidence interval (CI)) for the dietary restrictions were a younger age (p = 0.02), a higher level of education (p = 0.007), and a higher visceral sensitivity index (p = 0.009). Most (80%) of the patients displayed an inadequate calcium intake, and an abnormal result at dual-energy X-ray absorptiometry (DXA) scan accounting for low BMD was reported in 46 (51%) of them. Dietary restrictions (p = 0.03), and in particular avoiding dairy products (p = 0.001), were significant risk factors for a low BMD, along with female gender (p = 0.001), smoking (p = 0.04), and steroid abuse (p = 0.03). Almost all (86%) patients changed their diet after IBD diagnosis, as 8% believed that foods could have been a trigger for IBD and 37% that a proper diet was more important than drugs in controlling disease. Although 61% of the patients claimed to have received nutritional advice, 78% of the participants showed interest in receiving more. Conclusions: Dietary habits of IBD patients should be investigated by healthcare professionals as part of the routine visit. Clinicians are invited to provide nutritional recommendations to these patients in order to avoid unnecessary self-prescribed dietary restrictions. Full article

Background and Objectives: Menopause is a normal physiological change occurring at a woman’s mid-life. During this time, women experience vasomotor, physical and physiological problems, which reduce their quality of life. Many women are searching for different, alternative methods to reduce the severity of menopausal symptoms. Physical activity (PA) is one of the recommended methods to reduce menopausal symptoms. The purpose of this study was to investigate the association between specific domains (physical activity during leisure time, at work, during transportation and household activities) and the menopausal symptoms. Materials and Methods: We included 305 women aged 40–65 in the study. All participants were divided into three groups according to menopausal status. The research tools used were the International Physical Activity Questionnaire (IPAQ) to assess physical activity level in four domains and the Menopause Rating Scale (MRS) to assess the severity of menopausal symptoms. The data analysis was performed by Chi-square test and analysis of variance (ANOVA) with post hoc Tuckey test. Results: Menopausal stage was significantly associated with the total MRS score (p < 0.001) and specifically the urogenital and somato–vegetative subscores (p < 0.001). Physical activity was significantly associated (p < 0.001) with leisure time (according to IPAQ domains). Most postmenopausal women had high PA level (59.66%). Significantly less women with high PA levels had severe urogenital symptoms: 10.82% of participant with a low PA level, 11.15% with a moderate PA level and 4.26% with a high PA level (p = 0.046). Conclusions: Physical activity during leisure time is associated to menopausal symptoms in Polish women. Women with high and moderate PA levels have less severe menopausal symptoms compared to inactive women. Middle-aged women with low PA levels at work suffer from more severe somato–vegetative symptoms. Full article

Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development. Full article

Background and Objectives: The current study focuses on an eco-friendly and cost-effective method of Ephedra procera C. A. Mey. mediated green synthesis of silver nanoparticles as potential cytotoxic, antimicrobial and anti-oxidant agents. Materials and Methods: Plant aqueous extracts were screened for Total Phenolic (TPC), Total Flavonoid contents (TFC), Total Antioxidant Capacity (TAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging potentials. Total reducing power estimated by potassium ferricyanide colorimetric assay. The biosynthesized E. procera nanoparticles (EpNPs) were characterized by UV-spectroscopy, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction and Scanning electron microscopy. EpNPs were evaluated for their antimicrobial, bio-compatibility and cytotoxic potentials. Results: Initial phytocheimcal analysis of plant aqueous extract revealed TFC of 20.7 ± 0.21 µg/mg extract and TPC of 117.01 ± 0.78 µg/mg extract. TAC, DPPH free radical scavenging and reducing power were 73.8 ± 0.32 µg/mg extract, 71.8 ± 0.73% and 105.4 ± 0.65 µg/mg extract respectively. The synthesized EpNPs were observed to possess high cytotoxicity against HepG2 cancer cell lines with IC₅₀ (61.3 µg/mL) as compared aqueous extract with IC₅₀ of (247 µg/mL). EpNPs were found to be biocompatible and have less effect on human erythrocytes. EpNPs exhibited significant antioxidant potentials and exhibited considerable activity against Escherichia coli and Bacillus subtilis with Minimum Inhibitory Concentration (MICs) of 11.12 μg/mL and 11.33 μg/mL respectively. Fungal species Aspergillus niger and Aspergillus flavus were found susceptible to EpNPs. Conclusions: Results of the current study revealed that EpNPs exhibited considerable antibacterial, antifungal and cytotoxic potentials. Aqueous extract possesses significant anti-radical properties and thus can be useful in free radicals induced degenerative disorders. Full article

Background and objectives: Health systems all over the world are confronted with an alarming rise of cases in which individuals hesitate, delay, and even refuse vaccination, despite availability of quality vaccine services. In order to mitigate and combat this phenomenon, which are now defined by the World Health Organization (WHO) as vaccine hesitancy (VH), we must first understand the factors that lead to its occurrence in an era characterized by wide access to safe and effective vaccines. To achieve this, we conducted field testing of the Vaccine Hesitancy Scale (VHS), as it was developed by the Strategic Advisory Group of Experts Working Group (SAGE WG), in Cluj-Napoca city, Cluj County, Romania. The scale is designed to quantify VH prevalence in a population, establish which vaccines generate the highest percentage of hesitancy, and allow a qualitative assessment of the individual’s reasons for hesitance. Materials and Methods: We conducted an observational cross-sectional survey, which was comprised of descriptive, analytical, and qualitative elements regarding VH. The necessary sample size was 452 individuals. The VHS and Matrix of Determinants (recommended by SAGE WG) for reasons people gave to justify their hesitance, was interpreted by qualitative thematic analysis (QTA) to ensure the validity and reliability in detecting hesitancy across various cultural settings and permit global comparisons. Results: We found a VH of 30.3% and 11.7% of parents reported refusing to vaccinate their child. Among the VH responders, the varicella vaccine generated 35% hesitancy, measles vaccine 27.7%, Human Papillomavirus (HPV) 24.1%, and mumps vaccine 23.4%, respectively. The QTA values for percent agreement ranged from 91% to 100%. Cohen’s Kappa values ranged from 0.45 to 0.95. Contextual influences identified for VH were “media,” “leaders and lobbies,” and “perception of the pharmaceutical industry.” Individual and group influences for VH were “beliefs,” “knowledge,” and “risk/benefits (perceived).” Vaccine and vaccination specific issues for VH were “risk/benefit (rational)” and “health care practitioners (trustworthiness, competence).” Conclusions: One-third of the investigated population had expressed VH, and a further one-third of these had refused a vaccine for their child. Chicken Pox, Measles, Mumps, Rubella (MMR), and HPV vaccines generated the most hesitation. Negative information from the media was the most frequently evoked reason for VH. Full article

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility—with extensive first-pass metabolism—can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT₁₄) were found to be 178 ± 16, −21.4, and 85.5%, respectively. Long chain triglyceride (LCT₁₄) showed a 1.5-fold increased elimination half-life (p < 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p < 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT₁₄) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine. Full article

Background and objectives: Many studies indicate that the maternal diet is an important factor affecting human milk composition. Human milk composition among lactating women in Latvia, as well as the maternal diet during lactation, has not been sufficiently studied. The aim of this research was to assess dietary habits and macronutrient intake among lactating women in Latvia and to examine the effect of diet on human milk composition. Materials and Methods: Research was conducted between November 2016 and December 2017. Mature human milk samples (n = 61) along with a 72h food diary, a food frequency questionnaire (FFQ), and a questionnaire about maternal and infant characteristics were obtained from voluntary women who were recruited via an invitation published in a social media member group for nursing mothers. Fat content in human milk was determined by LVS ISO 2446:2008, protein content was determined by LVS EN ISO 8968-1:2014, lactose was determined by ISO 22662:2007, and the fatty acid profile was analyzed using gas chromatography. Dietary data were evaluated using the Finnish food composition database Fineli, release 19 (3 March 2018). Results: Median values for fat, protein, and lactose in mature human milk were 4.40%, 1.08%, and 6.52%, respectively. Predominant fatty acids in human milk were oleic acid (C18:1 n9c), palmitic acid (C16:0), and linoleic acid (C18:2 n6c) at 34.60%, 24.00%, and 11.00% of total fatty acids, respectively. The trans elaidic acid (C18:1 n9t) level was <0.10% in all human milk samples. Significant, positive associations (p < 0.05) were found between maternal dietary intake of linoleic, α-linolenic, docosahexaenoic, total cis-monounsaturated, total cis-polyunsaturated, and total n-6 and n-3 polyunsaturated fatty acids, the ratio of n-6/n-3, and the level of these fatty acids in human milk. Total energy and carbohydrate intake among participants were lower, but total fat, saturated fat, and sugar intake were higher than recommended. Protein, linoleic acid, and α-linolenic acid intake were adequate, but docosahexaenoic acid intake was noticeably lower than recommended. Women should be supported with information regarding their nutritional needs during lactation and the possible impact of diet on human milk composition. Conclusion: Macronutrient (fat, protein, and lactose) content in human milk is not affected by maternal diet. Conversely, the human milk fatty acid profile is affected by the immediate diet consumed by the mother. Habitual dietary habits can also impact the fatty acid profile of human milk. Full article

Background and Objectives: The key pathogenetic mechanism of glucose metabolism disorders, insulin resistance (IR), can be assessed using the Homeostasis Model Assessment of IR (HOMA-IR). However, its application in clinical practice is limited due to the absence of cut-offs. In this study, we aimed to define the cut-offs for the Czech population. Methods: After undergoing anthropometric and biochemical studies, the sample of 3539 individuals was divided into either nondiabetics, including both subjects with normal glucose tolerance (NGT, n = 1947) and prediabetics (n = 1459), or diabetics (n = 133). The optimal HOMA-IR cut-offs between subgroups were determined to maximize the sum of the sensitivity and specificity for diagnosing type 2 diabetes mellitus (T2DM) or prediabetes. The predictive accuracy was illustrated using receiver operating characteristic (ROC) curves. Logistic regression was performed to assess the association between a target variable (presence/absence of T2DM) depending on the HOMA-IR score as well as on the age and sex. Results: The HOMA-IR cut-off between nondiabetics and diabetics for both sexes together was 3.63, with a sensitivity of 0.56 and a specificity of 0.86. The area under the ROC curve was 0.73 for T2DM diagnosing in both sexes. The HOMA-IR cut-off between the NGT subjects and prediabetics was 1.82, with a sensitivity of 0.60 and a specificity of 0.66. Logistic regression showed that increased HOMA-IR is a risk factor for the presence of T2DM (odds ratio (OR) 1.2, 95% confidence interval (CI) 1.14–1.28, p < 0.0001). The predictive ability of HOMA-IR in diagnosing T2DM is statistically significantly lower in females (OR 0.66, 95% CI 0.44–0.98). The results are valid for middle-aged European adults. Conclusions: The results suggest the existence of HOMA-IR cut-offs signaling established IR. Introduction of the instrument into common clinical practice, together with the known cut-offs, may contribute to preventing T2DM. Full article

Background and objectives: Previous studies have shown anti-tumor activity of quercetin (QT). However, the low bioavailability of QT has restricted its use. This study aimed to assess the toxic effect of QT encapsulated in solid lipid nanoparticles (QT-SLNs) on the growth of MCF-7 human breast cancer cells. Materials and Methods: MCF-7 and MCF-10A (non-tumorigenic cell line) cell lines treated with 25 µmol/mL of QT or QT-SLNs for 48 h. Cell viability, colony formation, oxidative stress, and apoptosis were evaluated to determine the toxic effects of the QT-SLNs. Results: The QT-SLNs with appropriate characteristics (particle size of 85.5 nm, a zeta potential of −22.5 and encapsulation efficiency of 97.6%) were prepared. The QT-SLNs showed sustained QT release until 48 h. Cytotoxicity assessments indicated that QT-SLNs inhibited MCF-7 cells growth with a low IC₅₀ (50% inhibitory concentration) value, compared to the free QT. QT-SLNs induced a significant decrease in the viability and proliferation of MCF-7 cells, compared to the free QT. QT-SLN significantly increased reactive oxygen species (ROS) level and MDA contents and significantly decreased antioxidant enzyme activity in the MCF-7 cells. Following QT-SLNs treatment, the expression of the Bcl-2 protein significantly decreased, whereas Bx expression showed a significant increase in comparison with free QT-treated cells. Furthermore, The QT-SLNs significantly increased apoptotic and necrotic indexes in MCF-7 cells. Viability, proliferation, oxidative stress and apoptosis of MCF-10A cells were not affected by QT or QT-SLNs. Conclusions: According to the results of this study, SLN significantly enhanced the toxic effect of QT against human breast cancer cells. Full article

Background and objectives: Oxidative stress signalling plays a monumental role in inflammatory bowel disease (IBD). Reduction of oxidative stress might control inflammation, block tissue damage, and reverse natural history of IBD. We assessed the serum concentrations of free thiols (FT) and uric acid (SUA), together constituting a large part of nonenzymatic serum antioxidant capacity, as well as total antioxidant status (TAS) with reference to IBD phenotype, activity, co-occurrence of anemia, and treatment with azathioprine (AZA) and corticosteroids (CS). Additionally, we appraised the potential of uric acid, thiol stress, and TAS as mucosal healing (MH) markers in ulcerative colitis. Materials and methods: SUA, FT, and TAS were measured colorimetrically using, respectively, uricase, Ellman’s and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) methods. Results: The study group consisted of 175 individuals: 57 controls, 71 ulcerative colitis (UC), and 47 Crohn’s disease (CD) patients. When compared to controls, SUA levels were significantly lower in patients with CD, and FT and TAS levels were significantly lower in patients with CD and UC. In UC patients, SUA, FT, and TAS inversely correlated with the severity of bowel inflammation. As MH markers, SUA displayed better overall accuracy and higher specificity than FT. In active CD, FT, and SUA were significantly lower in patients with anemia. FT was significantly lower in patients treated with corticosteroids. Conclusions: IBD patients, regardless the disease phenotype, have systemic thiol stress, depleted total antioxidant capacity, and reduced concentrations of uric acid, reflecting, to various degrees, clinical and local disease activity as well as presence of anaemia, the most common extraintestinal manifestation of IBD. Evaluation of systemic total antioxidant status may be useful in noninvasive assessment of mucosal healing. Our findings on thiol stress provide an additional aspect on adverse effects of corticosteroids therapy. Full article

Background and objectives: Zingerone is an ingredient of ginger (Zingiber officinale) with different pharmacological activities. Several studies have investigated the effect of zingerone on various gastrointestinal diseases, including irritable bowel syndrome and diarrhea. This study is aimed to evaluate the effect of zingerone on ethanol-induced gastric ulcers in rats. Materials and Methods: Gastric ulcers were induced by ethanol (96%, 5 mL/kg, po) in male wistar rats and zingerone (50, 100, and 200 mg/kg) was administrated orally. Normal saline and ranitidine were used as negative and positive control, respectively. In this study, the number and length of ulcers, and malondialdehyde (MDA) and nitric oxide (NO) levels in stomach tissues were determined. Results: The findings showed that the mean number and length of gastric ulcers were significantly lower in zingerone-received groups than ethanol group (P < 0.05). The level of malondialdehyde was decreased in the stomach of zingerone groups (P < 0.05) compared to the ethanol group. In addition, zingerone treatment prevented the decrease of nitric oxide level by ethanol in the stomach tissue. Conclusions: The present study showed that zingerone has a protective effect on the ethanol-induced gastric ulcer, which may be due to its free radical scavenging activity. Full article

Background and objectives: High mortality and healthcare costs area associated with ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii (A. baumannii). The data concerning the link between multidrug-resistance of A. baumannii strains and outcomes remains controversial. Therefore, we aimed to identify the relation of risk factors for ventilator-associated pneumonia (VAP) and mortality with the drug resistance profiles of Acinetobacter baumannii (A. baumannii) and independent predictors of in-hospital mortality. Methods: A retrospective ongoing cohort study of 60 patients that were treated for VAP due to drug-resistant A. baumannii in medical-surgical intensive care units (ICU) over a two-year period was conducted. Results: The proportions of multidrug-resistant (MDR), extensively drug-resistant (XDR), and potentially pandrug-resistant (pPDR) A. baumannii were 13.3%, 68.3%, and 18.3%, respectively. The SAPS II scores on ICU admission were 42.6, 48.7, and 49 (p = 0.048); hospital length of stay (LOS) prior to ICU was 0, one, and two days (p = 0.036), prior to mechanical ventilation (MV)—0, 0, and three days (p = 0.013), and carbapenem use prior to VAP—50%, 29.3%, and 18.2% (p = 0.036), respectively. The overall in-hospital mortality rate was 63.3%. In MDR, XDR, and pPDR A. baumannii VAP groups, it was 62.5%, 61.3%, and 72.7% (p = 0.772), respectively. Binary logistic regression analysis showed that female gender (95% OR 5.26; CI: 1.21–22.83), SOFA score on ICU admission (95% OR 1.28; CI: 1.06–1.53), and RBC transfusion (95% OR 5.98; CI: 1.41–25.27) were all independent predictors of in-hospital mortality. Conclusions: The VAP risk factors: higher SAPS II score, increased hospital LOS prior to ICU, and MV were related to the higher resistance profile of A. baumannii. Carbapenem use was found to be associated with the risk of MDR A. baumannii VAP. Mortality due to drug-resistant A. baumannii VAP was high, but it was not associated with the A. baumannii resistance profile. Female gender, SOFA score, and RBC transfusion were found to be independent predictors of in-hospital mortality. Full article

Background and objectives: Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. Materials and Methods: We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein–protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. Results: A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan–Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. Conclusions: This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC. Full article

During the COVID-19 emergency, the medical operating protocols have been largely modified for reducing any type of contamination risk, for working in a safe way and for making the patient feel in a safe environment. Telemedicine, smart phones and apps could represent important devices for the community, in order to prevent virus trasmission and to perform quick diagnosis and management at medical offices. This manuscript could be useful for clinicians with regard to the current state of the effectiveness of the telephone triage in this COVID-19 epidemic period. Therefore, it could be an important starting point for future perspectives about telemedicine and virtual patient management. Full article

Scientific research in the medical field shows this constantly: health starts from the mouth. Having good oral health nowadays is not only aimed at tooth health, but as amply demonstrated in the literature, it is a starting point for the general health and well-being of our body. Retracing the latest scientific findings that demonstrate an interpolation between oral health, oral diseases, and systemic complications, literature support was brought to this manuscript. Oral health, as demonstrated, has potentially multi-organ systemic implications, and as the results of the recent literature demonstrate, these implications range from an insulin resistance, due to a periodontal disease, up to far more complex multi-organ systemic complications involving the cardiovascular system or even neurodegenerative pathology. Therefore, being able to improve oral health could have great systemic implications for the organism, for the prevention of pathologies, and therefore for society and for the quality of life in individuals. Full article

Oral manifestations are early and important clinical indicators of Human Immunodeficiency Virus (HIV) infection since they can occur in up to 50% of HIV-infected patients and in up to 80% of patients at the AIDS stage (<200 CD4⁺ T lymphocytes). Oral health is related to physical and mental well-being because the presence of some lesions can compromise dental aesthetics, and alter speech, chewing, and swallowing, thus impacting the quality of life of patients. For this reason, it is necessary to integrate, as part of the medical treatment of HIV-positive patients, the prevention, diagnosis, and control of oral health. It is essential that health professionals have the power to identify, diagnose, and treat oral pathologies through clinical characteristics, etiological agents, and risk factors, both local and systemic. A diagnosis at an early stage of injury allows optimizing and prioritizing oral treatments, especially in acute pathologies, such as gingivitis and necrotizing periodontitis. In this group of patients, the development of strategies for the prevention, control, and reduction of these pathologies must be prioritized in order to reduce morbidity and mortality in this group of patients. Full article

The ‘Focal Infection Era in Dentistry’ in the late 19th and early 20th century resulted in widespread implementation of tooth extraction and limited the progress of endodontics. The theory proposed that bacteria and toxins entrapped in dentinal tubules could disseminate systemically to remote body parts, resulting in many types of degenerative systemic diseases. This theory was eventually refuted due to anecdotal evidence. However, lately there has been increased interest in investigating whether endodontic disease could have an impact on general health. There are reviews that have previously been carried out on this subject, but as new data have emerged since then, this review aims to appraise the available literature investigating the dynamic associations between apical periodontitis, endodontic treatment, and systemic health. The available evidence regarding focal infection theory, bacteraemia and inflammatory markers was appraised. The review also collated the available research arguing the associations of apical periodontitis with cardiovascular diseases, diabetes mellitus, adverse pregnancy outcome and autoimmune disorders, along with the effect of statins and immunomodulators on apical periodontitis prevalence and endodontic treatment prognosis. There is emerging evidence that bacteraemia and low-grade systemic inflammation associated with apical periodontitis may negatively impact systemic health, e.g., development of cardiovascular diseases, adverse pregnancy outcomes, and diabetic metabolic dyscontrol. However, there is limited information supporting the effect of diabetes mellitus or autoimmune disorders on the prevalence and prognosis post endodontic treatment. Furthermore, convincing evidence supports that successful root canal treatment has a beneficial impact on systemic health by reducing the inflammatory burden, thereby dismissing the misconceptions of focal infection theory. Although compelling evidence regarding the association between apical periodontitis and systemic health is present, further high-quality research is required to support and establish the benefits of endodontic treatment on systemic health. Full article

Nonalcoholic fatty liver disease (NAFLD) is a new challenge in modern medicine, due to its high prevalence in the world. The pathogenesis of NAFLD is a complex dysmetabolic process, following the “multiple-hit” hypothesis that involves hepatocytes excessive accumulation of triglycerides, insulin resistance (IR), increased oxidative stress, chronic low-grade inflammatory response and lipotoxicity. In this review, we provide an overview of the interrelation of these processes, the link between systemic and local inflammation and the role of dysfunctional adipose tissue (AT) in the NAFLD development. Multiple extrahepatic triggers of the pathophysiological mechanisms of NAFLD are described: nutritional deficiency or malnutrition, unhealthy food intake, the dysfunction of the liver–gut axis, the involvement of the mesenteric adipose tissue, the role of adipokines such as adiponectin, of food intake hormone, the leptin and leptin resistance (LR) and adipose tissue’s hormone, the resistin. In addition, a wide range of intrahepatic players are involved: oxidative stress, fatty acid oxidation, endoplasmic reticulum stress, mitochondrial dysfunction, resident macrophages (Kupffer cells), neutrophils, dendritic cells (DCs), B and T lymphocytes contributing to the potential evolution of NAFLD to nonalcoholic steatohepatitis (NASH). This interdependent approach to complex dysmetabolic imbalance in NAFLD, integrating relevant studies, could contribute to a better clarification of pathogenesis and consequently the development of new personalized treatments, targeting de novo lipogenesis, chronic inflammation and fibrosis. Further studies are needed to focus not only on treatment, but also on prevention strategy in NAFLD. Full article

Periodontitis is a microbially driven host-mediated disease that leads to loss of periodontal attachment and bone. It is associated with elevation of systemic inflammatory markers and with the presence of systemic co-morbidities. Furthermore, periodontal treatment leads to a 24–48 h-long acute local and systemic inflammatory response. This systemic response might increase the burden of patients with compromised medical history and/or uncontrolled systemic diseases. The correlation between periodontitis and systemic diseases, the impact of periodontitis on the quality of life and public health, the effects of periodontal treatment on systemic health and disease, and the available methods to manage systemic inflammation after periodontal therapy are discussed. The main focus then shifts to a description of the existing evidence regarding the impact of periodontitis and periodontal treatment on systemic health and to the identification of approaches aiming to reduce the effect of periodontitis on systemic inflammation. Full article

There is very recent and strong evidence relating Fusobacterium nucleatum to colorectal cancer. In this narrative review, we update the knowledge about gingival dysbiosis and the characteristics of Fusobacterium nucleatum as one of the main bacteria related to periodontitis. We provide data on microbiome, epidemiology, risk factors, prognosis, and treatment of colorectal cancer, one of the most frequent tumours diagnosed and whose incidence increases every year. We describe, from its recent origin, the relationship between this bacterium and this type of cancer and the knowledge and emerging mechanisms that scientific evidence reveals in an updated way. A diagram provided synthesizes the pathogenic mechanisms of this relationship in a comprehensive manner. Finally, the main questions and further research perspectives are presented. Full article

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na⁺/K⁺ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs. Full article

Atherosclerosis is responsible for large cardiovascular mortality in many countries globally. It has been shown over the last decades that the reduction of atherosclerotic progression is a critical factor for preventing future cardiovascular events. Low-density lipoproteins (LDL) have been successfully targeted, and their reduction is one of the key preventing measures in patients with atherosclerotic disease. LDL particles are pivotal for the formation and progression of atherosclerotic plaques; yet, they are quite heterogeneous, and smaller, denser LDL species are the most atherogenic. These particles have greater arterial entry and retention, higher susceptibility to oxidation, as well as reduced affinity for the LDL receptor. Increased proportion of small, dense LDL particles is an integral part of the atherogenic lipoprotein phenotype, the most common form of dyslipidemia associated with insulin resistance. Recent data suggest that both genetic and epigenetic factors might induce expression of this specific lipid pattern. In addition, a typical finding of increased small, dense LDL particles was confirmed in different categories of patients with elevated cardiovascular risk. Small, dense LDL is an independent risk factor for cardiovascular diseases, which emphasizes the clinical importance of both the quality and the quantity of LDL. An effective management of atherosclerotic disease should take into account the presence of small, dense LDL in order to prevent cardiovascular complications. Full article

A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death. The term cytokine storm was first used in 1993 to describe the graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. It was then reused to define the adverse syndromes secondary to the administration of immunostimulating agents, such as anti-CD28 antibodies or bioengineered immune cells, i.e., CAR T-cell therapy. Currently, the concept of cytokine storm has been better elucidated and extended to the pathogenesis of many other conditions, such as sepsis, autoinflammatory disease, primary and secondary hemophagocytic lymphohistiocytosis, and multicentric Castleman disease. Moreover, cytokine storm has recently emerged as a key aspect in the novel Coronavirus disease 2019, as affected patients show high levels of several key pro-inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-α, IFN-γ, IP-10, GM-CSF, MCP-1, and IL-10, some of which also correlate with disease severity. Therefore, since the onset of the pandemic, numerous agents have been tested in the effort to mitigate the cytokine storm in COVID-19 patients, some of which are effective in reducing mortality, especially in critically ill patients, and are now becoming standards of care, such as glucocorticoids or some cytokine inhibitors. However, the challenge is still far from being met, and other therapeutic strategies are being tested in the hope that we can eventually overcome the disease. Full article

Background and objective: Telemedicine or telehealth services has been increasingly practiced in the recent years. During the COVID-19 pandemic, telemedicine turned into and indispensable service in order to avoid contagion between healthcare professionals and patients, involving a growing number of medical disciplines. Nevertheless, at present, several ethical and legal issues related to the practice of these services still remain unsolved and need adequate regulation. This narrative review will give a synthesis of the main ethical and legal issues of telemedicine practice during the COVID-19 pandemic. Material and Methods: A literature search was performed on PubMed using MeSH terms: Telemedicine (which includes Mobile Health or Health, Mobile, mHealth, Telehealth, and eHealth), Ethics, Legislation/Jurisprudence, and COVID-19. These terms were combined into a search string to better identify relevant articles published in the English language from March 2019 to September 2021. Results: Overall, 24 out of the initial 85 articles were considered eligible for this review. Legal and ethical issues concerned important aspects such as: informed consent (information about the risks and benefits of remote therapy) and autonomy (87%), patient privacy (78%) and confidentiality (57%), data protection and security (74%), malpractice and professional liability/integrity (70%), equity of access (30%), quality of care (30%), the professional–patient relationship (22%), and the principle of beneficence or being disposed to act for the benefit of others (13%). Conclusions: The ethical and legal issues related to the practice of telehealth or telemedicine services still need standard and specific rules of application in order to guarantee equitable access, quality of care, sustainable costs, professional liability, respect of patient privacy, data protection, and confidentiality. At present, telemedicine services could be only used as complementary or supplementary tools to the traditional healthcare services. Some indications for medical providers are suggested. Full article

Pain management is a crucial issue for athletes who train and compete at the highest performance levels. There are still evidence gaps for the use of analgesics for sports injuries despite the growing interest in training and competition settings. However, high-quality research is needed to determine the most appropriate and optimal timing and formulations in non-steroidal anti-inflammatory drug and opioid management, particularly given the strictness of anti-doping regulations. Indeed, the role of pharmacological therapy in reducing acute traumatic pain in athletes should still be addressed to minimize the timing of return to sport. Therefore, the aim of this comprehensive review was to summarize the current evidence about pain management in the setting of acute injury in elite athletes, providing the most informed strategy for pain relief and performance recovery. Full article

Background and Objectives: Sport-related musculoskeletal injuries (MSK-Is) are a common health issue in athletes that can lead to reduced performance. The aim of this scoping review was to synthetize available evidence on injury incidence rates (IIRs), types, and sites that affect the musculoskeletal (MSK) system of adult athletes. Materials and Methods: We performed a scoping review on the Pubmed database limiting our search to 33 Olympic sports. Results: We identified a total of 1022 papers, and of these 162 were examined in full for the purpose of this review. Archery was the sport with the highest risk of injuries to the upper extremities, marathons for the lower extremities, and triathlon and weightlifting for the body bust. In the majority of the sports examined, muscle/tendon strain and ligament sprain were the most common MSK-Is diagnoses, while athletics, karate, and football were the sports with the highest IIRs, depending on the methods used for their calculations. Conclusions: Our scoping review highlighted the general lack and dishomogeneity in the collection of data on MSK-Is in athletes. Full article

Diabetes mellitus is an increasingly prevalent chronic metabolic disease characterized by prolonged hyperglycemia that leads to long-term health consequences. It is estimated that impaired healing of diabetic wounds affects approximately 25% of all patients with diabetes mellitus, often resulting in lower limb amputation, with subsequent high economic and psychosocial costs. The hyperglycemic environment promotes the formation of biofilms and makes diabetic wounds difficult to treat. In this review, we present updates regarding recent advances in our understanding of the pathophysiology of diabetic wounds focusing on impaired angiogenesis, neuropathy, sub-optimal chronic inflammatory response, barrier disruption, and subsequent polymicrobial infection, followed by current and future treatment strategies designed to tackle the various pathologies associated with diabetic wounds. Given the alarming increase in the prevalence of diabetes, and subsequently diabetic wounds, it is imperative that future treatment strategies target multiple causes of impaired healing in diabetic wounds. Full article

Background and Objectives: Pregnant women are more likely to develop a more severe course of COVID-19 than their non-pregnant peers. There are many arguments for the safety and efficacy of COVID-19 vaccines in pregnant women. The aim of this study is to conduct a systematic review concerning the approach of pregnant women towards vaccination against COVID-19, with particular regard to determinants of vaccination acceptance. Materials and Methods: Articles were reviewed in which the aim was to evaluate—via a survey or questionnaire—the acceptance and decision to undergo vaccination against COVID-19. The articles were subjected to review according to recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). Results: In various studies, the percentage of pregnant women accepting the COVID-19 vaccine was between 29.7% and 77.4%. The strongest factors co-existing with the acceptance of the COVID-19 vaccination in pregnancy were trust in the importance and effectiveness of the vaccine, explicit communication about the safety of COVID-19 vaccines for pregnant women, acceptance of other vaccinations such as those for influenza, belief in the importance of vaccines/mass vaccination in one’s own country, anxiety about COVID-19, trust in public health agencies/health science, as well as compliance to mask guidelines. The remaining factors were older age, higher education, and socioeconomic status. Conclusions: This review allowed us to show that geographic factors (Asian, South American countries) and pandemic factors (different threats and risks from infection) significantly influence the acceptance of vaccines. The most significant factors affecting acceptance are those related to public awareness of the risk of infection, vaccine safety, and the way in which reliable information about the need and safety of vaccines is provided. Professional and reliable patient information by obstetricians and qualified medical personnel would significantly increase the level of confidence in vaccination against COVID-19. Full article

Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression. Full article

Hyperbaric oxygen therapy (HBOT) consists of using of pure oxygen at increased pressure (in general, 2–3 atmospheres) leading to augmented oxygen levels in the blood (Hyperoxemia) and tissue (Hyperoxia). The increased pressure and oxygen bioavailability might be related to a plethora of applications, particularly in hypoxic regions, also exerting antimicrobial, immunomodulatory and angiogenic properties, among others. In this review, we will discuss in detail the physiological relevance of oxygen and the therapeutical basis of HBOT, collecting current indications and underlying mechanisms. Furthermore, potential areas of research will also be examined, including inflammatory and systemic maladies, COVID-19 and cancer. Finally, the adverse effects and contraindications associated with this therapy and future directions of research will be considered. Overall, we encourage further research in this field to extend the possible uses of this procedure. The inclusion of HBOT in future clinical research could be an additional support in the clinical management of multiple pathologies. Full article

Bladder cancer (BCa) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. While the clinical approach to BCa has remained largely unchanged for many years, recent discoveries have paved the way to a new era of diagnosis and management of the disease. BCa-specific mortality started to decrease in the regions with a wide range of activities leading to greater social awareness of the risk factors and the decline in carcinogenic exposure. The urologic community refines the role of transurethral surgery towards more rigorous and high-quality techniques. New agents have been approved for patients with BCG failure who faced radical cystectomy so far. Although radical removal of the bladder is the gold standard for muscle invasive cancer management, the extent and clinical value of lymphadenectomy is currently heavily challenged in randomized trials. Furthermore, alternatives to perioperative chemotherapy have arisen to increase the likelihood of complete treatment delivery and successful oncological outcomes. Finally, improvements in molecular biology and our understanding of tumorigenesis open the era of personalized medicine in bladder cancer. In the present review, the status and future directions in bladder cancer epidemiology, diagnosis and management are thoroughly discussed. Full article

Background and Objectives: Procalcitonin (PCT) is positively associated with the severity of COVID-19 (including severe, critical, or fatal outcomes), but some of the confounding factors are not considered. The aim of this meta-analysis was to estimate the adjusted relationship between elevated procalcitonin on admission and the severity of COVID-19. Materials and Methods: We searched 1805 articles from PubMed, Web of Science, and Embase databases up to 2 April 2021. The articles were selected which reported the adjusted relationship applying multivariate analysis between PCT and the severity of COVID-19. The pooled effect estimate was calculated by the random-effects model. Results: The meta-analysis included 10 cohort studies with a total of 7716 patients. Patients with elevated procalcitonin on admission were at a higher risk of severe and critical COVID-19 (pooled effect estimate: 1.77, 95% confidence interval (CI): 1.38–2.29; I² = 85.6%, p < 0.001). Similar results were also observed in dead patients (pooled effect estimate: 1.77, 95% CI: 1.36–2.30). After adjusting for diabetes, the positive association between PCT and the severity of COVID-19 decreased. Subgroup analysis revealed heterogeneity between studies and sensitivity analysis showed that the results were robust. There was no evidence of publication bias by Egger’s test (p = 0.106). Conclusions: Higher procalcitonin is positively associated with the severity of COVID-19, which is a potential biomarker to evaluate the severity of COVID-19 and predict the prognosis. Full article

Background and Objectives: Symptomatic irreversible pulpitis in permanent mature teeth is a common indication for nonsurgical root canal treatment (NSRCT), but contemporary studies have reported on vital pulp therapy (VPT) applied in such teeth as a less invasive treatment. This systematic review assessed the outcomes of VPT, including partial and full pulpotomy performed with hydraulic calcium silicate cements (HCSCs) in permanent mature posterior teeth diagnosed with symptomatic irreversible pulpitis. Materials and Methods: The PRISMA guidelines were followed. The search strategy included PubMed^®, EMBASE, Cochrane library and grey literature electronic databases. The quality assessment of the identified studies followed the Cochrane Collaboration Risk of Bias, ROBINS-I and Newcastle–Ottawa Scale tools. Results: The search of primary databases identified 142 articles, of which 9 randomized controlled trials and 3 prospective cohort studies were selected for review. The risk-of-bias was assessed as ‘high’ or ‘serious’, ‘fair’, and ‘low’ for three, seven and two articles, respectively. One to five years after VPT using HCSCs, the success rates mostly ranged from 78 to 90%. Based on two articles, the outcomes of the VPT and NSRCT were comparable at one and five years. Despite the necessity for the intra-operative pulp assessment in VPT procedures, the majority of the studies did not fully report on this step or on the time needed to achieve hemostasis. Small sample sizes, of under 23 teeth, were reported in three studies. Conclusions: The reviewed 12 articles reported favorable outcomes of the VPT performed with HCSCs in permanent mature posterior teeth with symptomatic irreversible pulpitis, with radiographic success in the range of 81 to 90%. Two articles suggested comparable outcomes of the VPT and root canal treatment. Universal case selection and outcome criteria needs to be established for VPT when considered as an alternative to NSRCT. This evidence supports the need for further research comparing longer-term outcomes of both of the treatment modalities. Full article

Even though scientific literature shows numerous heath complications and performance decrements associated with rapid weight loss (RWL), its prevalence remains exceedingly high across various combat sports. The aim of this study was to thoroughly search the existing literature to explore the influence of RWL on kidney function in Olympic and non-Olympic combat sport athletes. PubMed and Web of Science were searched for the relevant studies. Only original articles published from 2005 onwards, written in English, that included healthy males and females who prompted ~5% weight loss within a week or less, were included in the study. Retrieved studies showed that creatinine, blood urea nitrogen and urine specific gravity values were significantly increased after RWL in the majority of the included studies. This observation indicates that RWL caused dehydration and subsequent acute kidney damage despite various degrees of weight lost during the RWL phase, which can lead to adverse events in other body systems. Alternative methods of weight reduction that prioritize athletes’ health should be considered. Full article

Sensitivity, which denotes the proportion of subjects correctly given a positive assignment out of all subjects who are actually positive for the outcome, indicates how well a test can classify subjects who truly have the outcome of interest. Specificity, which denotes the proportion of subjects correctly given a negative assignment out of all subjects who are actually negative for the outcome, indicates how well a test can classify subjects who truly do not have the outcome of interest. Positive predictive value reflects the proportion of subjects with a positive test result who truly have the outcome of interest. Negative predictive value reflects the proportion of subjects with a negative test result who truly do not have the outcome of interest. Sensitivity and specificity are inversely related, wherein one increases as the other decreases, but are generally considered stable for a given test, whereas positive and negative predictive values do inherently vary with pre-test probability (e.g., changes in population disease prevalence). This article will further detail the concepts of sensitivity, specificity, and predictive values using a recent real-world example from the medical literature. Full article

Medication-related osteonecrosis of the jaw (MRONJ) has become a well-known side effect of antiresorptive, and antiangiogenic drugs commonly used in cancer management. Despite a considerable amount of literature addressing MRONJ, it is still widely accepted that the underlying pathomechanism of MRONJ is unclear. However, several clinical and preclinical studies indicate that infection seems to have a major role in the pathogenesis of MRONJ. Although there is no conclusive evidence for the infection hypothesis yet, available data have shown a robust association between local infection and MRONJ development. This observation is very critical in order to implement policies to reduce the risk of MRONJ in patients under antiresorptive drugs. This critical review was conducted to collect the most reliable evidence regarding the link between local infection and MRONJ pathogenesis. Full article

Diabetic peripheral neuropathy (DPN) is associated with peripheral sensory and motor nerve damage that affects up to half of diabetes patients and is an independent risk factor for falls. Clinical implications of DPN-related falls include injury, psychological distress and physical activity curtailment. This review describes how the sensory and motor deficits associated with DPN underpin biomechanical alterations to the pattern of walking (gait), which contribute to balance impairments underpinning falls. Changes to gait with diabetes occur even before the onset of measurable DPN, but changes become much more marked with DPN. Gait impairments with diabetes and DPN include alterations to walking speed, step length, step width and joint ranges of motion. These alterations also impact the rotational forces around joints known as joint moments, which are reduced as part of a natural strategy to lower the muscular demands of gait to compensate for lower strength capacities due to diabetes and DPN. Muscle weakness and atrophy are most striking in patients with DPN, but also present in non-neuropathic diabetes patients, affecting not only distal muscles of the foot and ankle, but also proximal thigh muscles. Insensate feet with DPN cause a delayed neuromuscular response immediately following foot–ground contact during gait and this is a major factor contributing to increased falls risk. Pronounced balance impairments measured in the gait laboratory are only seen in DPN patients and not non-neuropathic diabetes patients. Self-perception of unsteadiness matches gait laboratory measures and can distinguish between patients with and without DPN. Diabetic foot ulcers and their associated risk factors including insensate feet with DPN and offloading devices further increase falls risk. Falls prevention strategies based on sensory and motor mechanisms should target those most at risk of falls with DPN, with further research needed to optimise interventions. Full article

Background and Objectives: In the era of the coronavirus disease 2019 (COVID-19) pandemic, the management of immunosuppressive (IS) therapy in kidney transplant (KT) recipients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires attention. It is not yet understood whether IS therapy may protect from the cytokine storm induced by SARS-CoV-2 infection or a temporary adjustment/withdrawal of IS therapy to restore the immune system may be necessary. We performed a systematic literature review to investigate the current management of IS therapy in KT recipients with COVID-1. Materials and Methods: Out of 71 articles published from 1 February 2020 until 30 October 2020, 554 KT recipients with SARS-CoV-2 infection were identified. Results: Modifications of IS therapy were based on the clinical conditions. For asymptomatic patients or those with mild COVID-19 symptoms, a “wait and see approach” was mostly used; a suspension of antimetabolites drugs (347/461, 75.27%) or mTOR inhibitors (38/48, 79.2%) was adopted in the majority of patients with symptomatic COVID-19 infections. For CNIs, the most frequent attitude was their maintenance (243/502, 48.4%) or dose-reduction (99/502, 19.72%) in patients asymptomatic or with mild COVID-19 symptoms, while drug withdrawal was the preferred choice in severely symptomatic patients (160/450, 31.87%). A discontinuation of all IS drugs was used only in severely symptomatic COVID-19 patients on invasive mechanical ventilation. Renal function remained stable in 422(76.17%) recipients, while 49(8.84%) patients experienced graft loss. Eight (1.44%) patients experienced a worsening of renal function. The overall mortality was 21.84%, and 53(9.56%) patients died with functioning grafts. Conclusion: A tailored approach to the patient has been the preferred strategy for the management of IS therapy in KT recipients, taking into account the clinical conditions of patients and the potential interactions between IS and antiviral drugs, in the attempt to balance the risks of COVID-19-related complications and those due to rejection or graft loss. Full article

Background and Objectives: Long COVID defines a series of chronic symptoms that patients may experience after resolution of acute COVID-19. Early reports from studies with patients with long COVID suggests a constellation of symptoms with similarities to another chronic medical illness—myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A review study comparing and contrasting ME/CFS with reported symptoms of long COVID may yield mutualistic insight into the characterization and management of both conditions. Materials and Methods: A systemic literature search was conducted in MEDLINE and PsycInfo through to 31 January 2021 for studies related to long COVID symptomatology. The literature search was conducted in accordance with PRISMA methodology. Results: Twenty-one studies were included in the qualitative analysis. Long COVID symptoms reported by the included studies were compared to a list of ME/CFS symptoms compiled from multiple case definitions. Twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study. Conclusions: Early studies into long COVID symptomatology suggest many overlaps with clinical presentation of ME/CFS. The need for monitoring and treatment for patients post-COVID is evident. Advancements and standardization of long COVID research methodologies would improve the quality of future research, and may allow further investigations into the similarities and differences between long COVID and ME/CFS. Full article

Pain is managed using a biopsychosocial approach and pharmacological and non-pharmacological treatments. Transcutaneous electrical nerve stimulation (TENS) is a technique whereby pulsed electrical currents are administered through the intact surface of the skin with the intention of alleviating pain, akin to ‘electrically rubbing pain away’. Despite over 50 years of published research, uncertainty about the clinical efficacy of TENS remains. The purpose of this comprehensive review is to critically appraise clinical research on TENS to inform future strategies to resolve the ‘efficacy-impasse’. The principles and practices of TENS are described to provide context for readers unfamiliar with TENS treatment. The findings of systematic reviews evaluating TENS are described from a historical perspective to provide context for a critical evaluation of factors influencing the outcomes of randomized controlled trials (RCTs); including sample populations, outcome measures, TENS techniques, and comparator interventions. Three possibilities are offered to resolve the impasse. Firstly, to conduct large multi-centered RCTs using an enriched enrolment with randomized withdrawal design, that incorporates a ‘run-in phase’ to screen for potential TENS responders and to optimise TENS treatment according to individual need. Secondly, to meta-analyze published RCT data, irrespective of type of pain, to determine whether TENS reduces the intensity of pain during stimulation, and to include a detailed assessment of levels of certainty and precision. Thirdly, to concede that it may be impossible to determine efficacy due to insurmountable methodological, logistical and financial challenges. The consequences to clinicians, policy makers and funders of this third scenario are discussed. I argue that patients will continue to use TENS irrespective of the views of clinicians, policy makers, funders or guideline panel recommendations, because TENS is readily available without prescription; TENS generates a pleasant sensory experience that is similar to easing pain using warming and cooling techniques; and technological developments such as smart wearable TENS devices will improve usability in the future. Thus, research is needed on how best to integrate TENS into existing pain management strategies by analyzing data of TENS usage by expert-patients in real-world settings. Full article

Both laboratory investigations and body composition quantification measures (e.g., computed tomography, CT) portray muscle loss in symptomatic Coronavirus disease 2019 (COVID-19) patients. Muscle loss is associated with a poor prognosis of the disease. The exact mechanism of muscle damage in COVID-19 patients, as well as the long-term consequences of muscle injury in disease survivors, are unclear. The current review briefly summarizes the literature for mechanisms, assessment measures, and interventions relevant to skeletal muscle insult in COVID-19 patients. Muscle injury is likely to be attributed to the cytokine storm, disease severity, malnutrition, prolonged physical inactivity during intensive care unit (ICU) stays, mechanical ventilation, and myotoxic drugs (e.g., dexamethasone). It has been assessed by imaging and non-imaging techniques (e.g., CT and electromyography), physical performance tests (e.g., six-minute walk test), anthropometric measures (e.g., calf circumference), and biomarkers of muscle dystrophy (e.g., creatine kinase). Interventions directed toward minimizing muscle loss among COVID-19 patients are lacking. However, limited evidence shows that respiratory rehabilitation improves respiratory function, muscle strength, quality of life, and anxiety symptoms in recovering older COVID-19 patients. Neuromuscular electrical stimulation may restore muscle condition in ICU-admitted patients, albeit empirical evidence is needed. Given the contribution of malnutrition to disease severity and muscle damage, providing proper nutritional management for emaciated patients may be one of the key issues to achieve a better prognosis and prevent the after-effects of the disease. Considerable attention to longer-term consequences of muscle injury in recovering COVID-19 patients is necessary. Full article

Idiopathic inflammatory myopathies, including polymyositis (PM), dermatomyositis (DM), and clinically amyopathic DM (CADM), are a diverse group of autoimmune diseases characterized by muscular involvement and extramuscular manifestations. Interstitial lung disease (ILD) has major pulmonary involvement and is associated with increased mortality in PM/DM/CADM. The management of PM-/DM-/CADM-associated ILD (PM/DM/CADM-ILD) requires careful evaluation of the disease severity and clinical subtype, including the ILD forms (acute/subacute or chronic), because of the substantial heterogeneity of their clinical courses. Recent studies have highlighted the importance of myositis-specific autoantibodies’ status, especially anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl tRNA synthetase (ARS) antibodies, in order to evaluate the clinical phenotypes and treatment of choice for PM/DM/CADM-ILD. Because the presence of the anti-MDA5 antibody is a strong predictor of a worse prognosis, combination treatment with glucocorticoids (GCs) and calcineurin inhibitors (CNIs; tacrolimus (TAC) or cyclosporin A (CsA)) is recommended for patients with anti-MDA5 antibody-positive DM/CADM-ILD. Rapidly progressive DM/CADM-ILD with the anti-MDA5 antibody is the most intractable condition, which requires immediate combined immunosuppressive therapy with GCs, CNIs, and intravenous cyclophosphamide. Additional salvage therapies (rituximab, tofacitinib, and plasma exchange) should be considered for patients with refractory ILD. Patients with anti-ARS antibody-positive ILD respond better to GC treatment, but with frequent recurrence; thus, GCs plus immunosuppressants (TAC, CsA, azathioprine, and mycophenolate mofetil) are often needed in order to achieve favorable long-term disease control. PM/DM/CADM-ILD management is still a therapeutic challenge for clinicians, as evidence-based guidelines do not exist to help with management decisions. A few prospective clinical trials have been recently reported regarding the treatment of PM/DM/CADM-ILD. Here, the current knowledge on the pharmacologic managements of PM/DM/CADM-ILD was mainly reviewed. Full article

In the last two decades, three unknown pathogens have caused outbreaks, generating severe global health concerns. In 2003, after nucleic acid genotyping, a new virus was named severe acute respiratory syndrome coronavirus (SARS-CoV). After nine years, another coronavirus emerged in the middle east and was named MERS-CoV (Middle East Respiratory Syndrome—Coronavirus). Finally, in December 2019, a new unknown coronavirus was isolated from a cluster of patients and was named SARS-CoV-2 (COVID-19, coronavirus disease 2019). This review aims to propose a complete overview of autopsy in the three coronaviruses over the past two decades, showing its pivotal role in the management of unknown diseases. A total of 116 studies fulfilled the inclusion criteria: 14 studies were collected concerning SARS-CoV (87 autopsy reports, from Asian and American countries), 2 studies for MERS-CoV (2 autopsy reports, from Middle-East Asian countries), and 100 studies on SARS-CoV-2 (930 autopsy reports). Analyzing the data obtained on COVID-19, based on the country criterion, a large number of post-mortem investigation were performed in European countries (580 reports), followed by American countries (251 reports). It is interesting to note that no data were found from the Oceanic countries, maybe because of the minor involvement of the outbreak. In all cases, autopsy provided much information about each unknown coronavirus. Despite advanced technologies in the diagnostic fields, to date, autopsy remains the gold standard method to understand the biological features and the pathogenesis of unknown infections, especially when awareness of a pathogen is restricted and the impact on the healthcare system is substantial. The knowledge gained through this technique may positively influence therapeutic strategies, ultimately reducing mortality. Full article

Background and Objectives: Palatal expansion is a common orthodontic technique able to increase the transverse changes for subjects with constricted maxillary arches. The aim of the present investigation was to evaluate through a systematic review the tomography effectiveness of different palatal expander approaches. Materials and Methods: The database used to perform the screening and determine the eligibility of the clinical papers was PubMed (Medline). Results: The database search included a total of 284 results, while 271 articles were excluded. A total of 14 articles were included for the qualitative assessment. Conclusions: The effectiveness of the present studies reported that skeletal expansion was a useful approach to increase the transverse changes for subjects with constricted maxillary arches. Full article

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient’s diet, amount of exercise, and renal function. Full article

Background and Objectives: Artemisia is one of the most widely distributed genera of the family Astraceae with more than 500 diverse species growing mainly in the temperate zones of Europe, Asia and North America. The plant is used in Chinese and Ayurvedic systems of medicine for its antiviral, antifungal, antimicrobial, insecticidal, hepatoprotective and neuroprotective properties. Research based studies point to Artemisia’s role in addressing an entire gamut of physiological imbalances through a unique combination of pharmacological actions. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes are some of the major phytochemicals of the genus. Notable among the phytochemicals is artemisinin and its derivatives (ARTs) that represent a new class of recommended drugs due to the emergence of bacteria and parasites that are resistant to quinoline drugs. This manuscript aims to systematically review recent studies that have investigated artemisinin and its derivatives not only for their potent antiviral actions but also their utility against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Materials and Methods: PubMed Central, Scopus and Google scholar databases of published articles were collected and abstracts were reviewed for relevance to the subject matter. Conclusions: The unprecedented impact that artemisinin had on public health and drug discovery research led the Nobel Committee to award the Nobel Prize in Physiology or Medicine in 2015 to the discoverers of artemisinin. Thus, it is clear that Artemisia’s importance in indigenous medicinal systems and drug discovery systems holds great potential for further investigation into its biological activities, especially its role in viral infection and inflammation. Full article

Epidural hematomas (EDHs) and subdural hematomas (SDHs), or so-called extra-axial bleedings, are common clinical entities after a traumatic brain injury (TBI). A forensic pathologist often analyzes cases of traumatic EDHs or SDHs due to road accidents, suicides, homicides, assaults, domestic or on-the-job accidents, and even in a medical responsibility scenario. The aim of this review is to give an overview of the published data in the medical literature, useful to forensic pathologists. We mainly focused on the data from the last 15 years, and considered the most updated protocols and diagnostic-therapeutic tools. This study reviews the epidemiology, outcome, and dating of extra-axial hematomas in the adult population; studies on the controversial interdural hematoma are also included. Full article

Background and Objectives: Mast cell disorders comprise a wide spectrum of syndromes caused by mast cells’ degranulation with acute or chronic clinical manifestations. Materials and Methods: In this review article we reviewed the latest findings in scientific papers about mast cell disorders with a particular focus on mast cell activation syndrome and mastocytosis in pediatric age. Results: Patients with mast cell activation syndrome have a normal number of mast cells that are hyperreactive upon stimulation of various triggers. We tried to emphasize the diagnostic criteria, differential diagnosis, and therapeutic strategies. Another primary mast cell disorder is mastocytosis, a condition with a long-known disease, in which patients have an increased number of mast cells that accumulate in different regions of the body with different clinical evolution in pediatric age. Conclusions: Mast cell activation syndrome overlaps with different clinical entities. No consensus was found on biomarkers and no clearly resolutive treatment is available. Therefore, a more detailed knowledge of this syndrome is of fundamental importance for a correct diagnosis and effective therapy. Full article