Mushrooms have long rich history in folk medicine, traditional and functional foods due to high content of dietary myco-nutrients. Currently, there is increased interest in finding appropriate food-grade green ex-traction systems capable of extracting these bioactive compounds from dietary mushrooms for applica-tions in various food, pharmacological or nutraceutical formulations. Herein, we evaluated a modified Swiss water process (SWP) method using alkaline and acidic pH at low and high temperature under pressurized conditions as a suitable green food grade solvent to obtained extracts enriched with my-co-nutrients (dietary phenolics, total antioxidants (TAA), vitamins, and minerals) from Chaga. Ultra-high performance liquid chromatography coupled to high resolution accurate mass tandem mass spectrometry (UHPLC-HRAMS-MS/MS) was used to assess the phenolic compounds and vitamin levels in the extracts, while inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the mineral con-tents. Over twenty phenolic compounds were quantitatively evaluated in the extracts and the highest total phenolic content and antioxidant activity was observed at pH11.5 at 100°C. The most abundant phenolic compounds present in Chaga extracts included phenolic acids such as protocatechuic acid 4-glucoside (0.7-1.08µg/mL), syringic acid (0.62-1.18µg/mL), and myricetin (0.68-1.3µg/mL). Vitamins are being reported for the first time in Chaga. pH 2.5 at 100°C treatment shows superior effects in extracting the B vitamins whereas pH 2.5 at 60 and 100°C treatments were outstanding for extraction of total fat-soluble vitamins. Vitamin E content was the highest for the fat-soluble vitamins in the Chaga extract under acidic pH (2.5) and high temp. (100°C) and ranges between 50 to 175 µg/100g Chaga. Antioxidant minerals ranged from 85.94 µg/g (pH7 at 100°C) to 113.86 µg/g DW (pH2.5 at 100°C). High temperature 100°C and a pH of 2.5 or 9.5. The treatment of pH11.5 at 100°C was the most useful for recovering phenolics and antioxidants from Chaga including several phenolic compounds reported for the first time in Chaga. SWP is being proposed herein for the first time as a novel, green food-grade solvent system for the extraction of myco-nutrients from Chaga and have potential applications as a suitable approach to extract nutrients from other matrices. Chaga extracts enriched with bioactive myconutrients and antioxidants may be suitable for further use or applications in the food and nutraceutical industries.

Background. January 2021 marked one year since the start of COVID-19 pandemic: it is the time of intermediate conclusions. Objective. To evaluate CFR and IFR due to COVID-19 in various countries and territories, and to study if parameters of a population age affect CFR and IFR. Material and Methods. The databases of 219 countries were collected on the Worldometers, Index Mundi, Country Meters and World Bank websites. The processing of data was divided into two parts: the first part dealt with the calculation and analysis of CFR while the second, the calculation and analysis of IFR. Results. The calculations revealed that in 74 out of 219 countries, CFR was less than 1.00 %, in 69 countries it varied between 1.00 % and 2.00 %, and in 76 countries it was more than 2.00 %. The calculation of IFR revealed that in 183 countries, IFR was less than 1.00 %, in 22 countries IFR was between 1.00 % and 2.00 %, and only in 14 out of 219 countries IFR was more than 2.00 %. A correlation between IFR and parameters of a population age was found: the less median age and the percentage of 'aged' people – the less value of IFR, although, there was no correlation between parameters of a population age and CFR. Conclusion. The global health care system has gone through a year of serious trial caused by COVID-19 and appeared to have emerged victorious. In the majority of countries analyzed, the parameters of mortality due to COVID-19 were at a low level. So, there seems to be an objective basis for optimism and hope for an early end to the pandemic.

The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options for tested individuals and their family members. We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing with positive reports. We reviewed positive results with respect to the different levels of information provided in the reports; risk estimation and management, cascade family testing, information from secondary findings and actionable information for treatment decision-making. A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high (BRCA1, BRCA2, PALB2, PTEN, TP53), moderate (ATM, CHEK2, NBN), low (BARD1, BRIP1, CHEK2, MLH1, MSH2, MSH6, NF1, RAD51C) and with insufficient evidence for breast cancer risk genes (FANCA, FANCM, NBN, MRE11, PMS2, RAD50, RAD51B, XRCC2, MUTYH), respectively. 6.7% of individuals were double heterozygotes with two pathogenic variants. Germline findings in 92% of individuals are linked to evidence-based treatment information and receive risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

INTRODUCTION. The most common cause of eating non-food items (pica) is specific deficiencies of minerals, such as iron. This study aimed to assess the relationship between Pica and Iron deficiency anemia among pregnant women. METHODS. The study was conducted in the out-patient department, antenatal Clinic at East Jeddah Hospital from July to September 2020. Design: A quantitative descriptive correlation design. Sample size: A total of 400 pregnant women, included anemic pregnant women, ≥ 18 years old, with singleton fetus and iron deficiency anemia. RESULTS. The mean age was 32.2 ± 6.6, half of the participants reported food cravings. Ice was the main item in pica followed by clay and chalk. Two-thirds had pica, more than half during the 1st trimester. There is a statistically significant relationship between pica and the history of a family member, parity, and gravidity at (P< 0,001, P <0,001, P <0,005) respectively. Hb and hematocrit in relation to pica reflected a statistically significant relationship (P< 0,001) and (P< 0,001), respectively. The symptoms attributed to iron deficiency were significantly associated with pica (P< 0,006). CONCLUSION. The pica and iron deficiency anemia had a significant association with pregnant women in EJH. RECOMMENDATION. The follow-up visits should integrate the food behavior inquiry to check if the pica existing with anemic or non-anemic pregnant women. Also, increase the awareness among midwives-nurses about the prevalence of pica and iron deficiency anemia among pregnant women.

Epilepsy is characterized by repeated spontaneous reactions caused by hyper-excitability and neurons firing in high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients and nearly 30% of individuals are refractory to treatment of antiepileptic drugs. Therefore, there is an urgent need to develop new medicines to manage and control the refractory epilepsy. Cannabinoid ligands including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands may serve as the novel candidates for this need. Cannabinoid systems appear to regulating seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including a rat pilocarpine model of acquired epilepsy, in vitro hippocampal neuronal culture models of acquired epilepsy and status epilepticus, a pentylenetetrazole model of myoclonic seizures in mice and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. For this reason, we summarize the relationship between brain CB2 receptors and seizures, and emphasize the potential mechanisms of their therapeutic effects involving affecting neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.

(1) Background:A BMI &gt; 25 is the most decisive, albeit modifiable,risk factors for knee osteoarthritis (OA). This study aimed at assessing the efficacy of intra-articular injections of hybrid hyaluronic acid (HA) complexes (Synovial® H-L)for the treatment of kneeOA in overweight patientsin terms ofdisease severity, cardiocirculatory capacity, and quality of life. (2) Materials: In this single-site, open-label, prospective trial, 37 patients with symptomatic knee OA were assessed at baseline and 3 months after ultrasound-guided intra-articular injection of hybrid HA complexes (Synovial® H-L). (3) Results: Primary variables displaying a statistically significant improvement after treatment were pain (NRS), disease severity (WOMAC), and cardiopulmonary capacity a(6-Minute Walk Test). Among secondary variables, quality of life (SF-12) improved significantly, as did analgesic intake for pain control. No statistically significant difference was observed in body fat and muscle mass percentage measured by bioelectrical impedance analysis. (4) Conclusions:Intra-articular hybrid HA injections are significantly effective in improving OA-related disease severity, cardiopulmonary function, and analgesic intake. This supports the role of hybrid HA viscosupplementation as a non-pharmacological treatment to relieve pain, reduce disability and improve quality of life, and limit the risk of polypharmacy in overweight patients with knee OA.

Background: The present retrospective study was designed to evaluate the relative diagnostic utility of breast-specific gamma imaging (BSGI) and breast magnetic resonance imaging (MRI) as means of evaluating female breast cancer patients in China. Methods: A total of 229 malignant breast cancer patients underwent ultrasound, mammography, BSGI, and MRI between January 2015 and December 2018 for initial tumor staging. Of these patients, 73 were subsequently treated via definitive breast surgery following neoadjuvant chemotherapy (NAC), of whom 17 exhibited a complete pathologic response (pCR) to NAC. Results: BSGI and MRI were associated with respective 76.8% and 69.6% sensitivity values as a means of detecting residual tumors following NAC, while both of these approaches exhibited comparable specificity in this diagnostic context (58.8% vs 70.6%, P=0.473). Conclusion: These results demonstrate that BSGI is a useful auxiliary approach to evaluating pCR to NAC treatment.

Background. A previous study demonstrated the performance of the Salivette® (SARSTEDT, Numbrecht, Germany) as a homogeneous saliva collection system to diagnose COVID-19 by RT-qPCR, notably for symptomatic and asymptomatic patients. However, for convalescent patients, the corroboration of molecular detection of SARS-CoV-2 in paired nasopharyngeal swabs (NPS) and saliva samples was unsatisfactory. Objectives. The aim of the present work was to assess the concordance level of SARS-CoV-2 detection between paired sampling of NPSs and saliva collected with Salivette® at two time points, with ten days of interval. Results. A total of 319 paired samples from 145 outpatients (OP) and 51 healthcare workers (HW) were collected. Due to significant waiting rate at hospital, most of the patients ate and/or drank in waiting their turn. Consequently, a mouth washing was systematically proposed prior saliva collection. None of the HW were diagnosed SARS-CoV-2 positive using NPS or saliva specimens at both time points (n=95) by RT-qPCR. The virus was detected in 56.3% (n=126/224) of the NPS samples from OP, but solely 26.8% (n=60/224) of the paired saliva specimens. The detection of the internal cellular control, the human RNase P, in more than 98% of the saliva samples, underlined that the low sensitivity of saliva specimens (45.2%) for SARS-CoV-2 detection was not attributed to an improper saliva sample storing or RNA extraction. Conclusions. Then, the mouth washing decreased viral load of buccal cavity conducting to impairment of SARS-CoV-2 detection. Viral loads in saliva neo-produced appeared insufficient for molecular detection of SARS-CoV-2. At the time that saliva tests could be a rapid, simple and noninvasive strategy to assess on large scale schooled children in France, the determination of the performance of saliva collection become imperative to standardize procedures.

Background: Asthma is ranked 16th among the leading causes of years lived with disability and 28th among the leading causes of disease in the world. Metered dose inhaler remains the principal route for drug administration and it has greater advantages over systemic treatment. In routine use, however, a vast majority of patients make inhalation errors. Suboptimal inhaler technique worsens health outcomes, with poor disease control, and increases the risk of hospitalization. This study aimed to assess practice metered-dose inhalation techniques and associated factors among asthmatic patients at Debre Markos comprehensive specialized hospital, East Gojjam, Amhara region, Ethiopia. Methods: Prospective cross-sectional study was conducted from July 15 to August 30/ 2020. Data were collected through a semi-structured questioner. The data was analyzed using SPSS version 25. Associations between dependent and independent variables were assessed by using binary and multiple logistic regressions. P-values less than 0.05 were considered to be statistically significant in all cases. Results presented in tables, figures, numbers, and percentages. Result: A total of 166 patients had involved in the study, of which 52.4% were females. One hundred eleven (66.9%) of participants had good knowledge of asthma and inhalational techniques with the rest of them had poor knowledge. One hundred eight (65.1%) patients had effective practice on metered-dose inhaler use techniques. Participant's knowledge regarding asthma and meter dose inhaler and marital status has a significant association with their practice of metered-dose inhaler techniques with P-value 0.001 and 0.006 respectively. Conclusion: In this study, most participants are suffering from asthma for a long duration and they have repeated exacerbation. Around two-thirds of patients had good knowledge regarding asthma and meter dose inhaler and practice on metered-dose inhaler techniques. Participants who had poor knowledge and who were unmarried had poor practice on tech metered-dose inhaler techniques. Health education and counseling services should be consistently provided to the clients regarding the proper steps of inhalers use.

Nutrigenetics concerns individual differences in the reaction to food based on the genetic factors. Nutrigenomics analyses direct influences of nutrients on gene expression. Both terms are explained in our review article. Nutrigenetics and nutrigenomics require a deep understanding of nutrition, genetics and biochemistry and of new ‘omic’ technologies. It is often difficult to appreciate their relevance in the practice of preventive approaches for optimizing health, delaying onset of disease and diminishing its severity. This paper represents a review about the current research on Nutrigenomics and Nutrigenetics, and provide scientific data for a new integrated clinical approach.

Several types of soft tissue sarcomas have peripheral infiltrative growth characteristics called tail-like lesions. The efficacy of neoadjuvant therapy for tumors with tail-like lesions has not been elucidated. From 2012 to 2019, we analyzed 36 patients with soft tissue sarcoma with tail-like lesions treated with neoadjuvant therapy, including chemotherapy, radiotherapy, or both. The ef-fect of neoadjuvant therapy on the tail sign was investigated by analyzing the change in tail-like lesions during neoadjuvant therapy and histological responses. The median length of the tail-like lesion reduced from 29.5 mm at initiation to 19.5 mm after neoadjuvant therapy. The extent of shrinkage in tail-like lesion was related to the histopathological responses in the main part. Com-plete disappearance of the tail-like lesion was observed in 12 patients; however, it was not related to achieving a microscopically negative margin. The oncologic outcomes did not significantly differ between cases with complete disappearance of tail-like lesions or not. This study indicated the shrinkage of tail-like lesions did not have significant effect on complete resection or improve-ment of clinical outcomes. A more comprehensive evaluation is needed to elaborate on the surgi-cal strategy.

International guidelines are published in oncology to provide standardized information and fertility preservation (FP) care for adults and children with cancer. For benign gynecologic diseases (BGD), many recommendations are based on data coming from oncofertility studies rather than studies with a stronger and broader evidence base. The purpose of the study was to conduct a modified Delphi process for generating FP guidelines for BGD. A steering committee identified 42 potential FP practices for BGD. Then 114 key stakeholders were asked to participate in a modified Delphi process via two online survey rounds and a final meeting. Consensus was reached for 28 items. Among them, stakeholders rated age-specific information concerning the risk of diminished ovarian reserve after surgery as important but rejected proposals setting various upper and lower age limits for FP. All women should be informed about the benefit/risk balance of oocyte vitrification, in particular about the likelihood of live birth according to age. FP should not be offered in rASRM stages I and II endometriosis without endometriomas. These guidelines could be useful for gynecologists to identify situations at risk of infertility and to better inform women with BGDs who might need personalized counseling for FP.

In this study, the effects of music therapy on anxiety for patients undergoing regional anaesthesia in an operating room was succinctly investigated. This investigation was largely based on the adapted Hospital Anxiety and Depression Score (HADS) and Spielberger State-Trait Anxiety Inventory (STAI-S), of patients undergoing regional anaesthesia in an operating room. A randomized control trial was performed on 90 patients due for surgery. The selected patients for regional anaesthesia were allocated to either the music therapy group who listened to music using headphones for the entire surgery or the no-treatment control group. Based on the findings, it has been conclusively demonstrated that music can decrease the patient's anxiety level. According to the socio-demographic evaluation, elderly patients have the highest stress hormones levels when compared to young patients. Although elderly patients are more likely to choose religious songs to help them relax, cortisol analysis revealed an increase in cortisol levels among the elderly compared with younger patients. As a result, music is especially important to be delivered to elderly patients. Nonetheless, there is no restriction against administering music to elderly patients because evidence from the Hospital Anxiety and Depression Score (HADS) and State-Trait Anxiety Inventory (STAI-S) has shown that music helps to shift their attention away from pain and complications and makes them feel tranquil. Similarly, the HADS and modified Spielberger STAI (STAI-S) analyses demonstrate a substantial outcome for both groups, with respondents responding positively. The study found that listening to music during regional anaesthesia might help people feel less worried.

Background: this RCT assesses the 18 months clinical outcomes after regenerative therapy of periimplantitis lesions using either an electrolytic method (EC) to remove biofilms or a combination of powder spray and electrolytic method (PEC). Materials and Methods: Twenty-four patients (24 implants) suffering from periimplantitis were randomly treated by EC or PEC followed by augmentation and submerged healing. Probing pocket depth (PPD), Bleeding on Probing (BoP), suppuration and standardized radiographs were assessed before surgery (T0), 6 months after augmentation (T1), 6 (T2) and 12 (T3) months after replacement of the restoration. Results: Mean of PPD changed from 5.8 ± 1.6 mm (T0) to 3.1 ± 1.4 mm (T3). While BoP and suppuration at T0 was 100 % BoP decreased at T2 to 36.8 % and at T3 to 35.3 %. Suppuration could be found 10.6% at T2 and 11.8% at T3. Radiologic bone level measured from the implant shoulder to the first visible bone to implant contact was 4.9 ± 1.9 mm at me-sial and 4.4 ± 2.2 mm at distal sites (T0) and 1.7 ± 1.7 mm and 1.5 ± 17 mm at T3. Conclusions: Significant radiographic bone fill and improvement of clinical parameters were demonstrated 18 months after therapy.

Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.

Background: It is clear that breastfeeding is the gold standard of infant feeding because of the many advantages it offers to both the child and the mother. Objective: to identity the main reasons for cessation breastfeeding declares by the mother themselves during the first year. Design: A prospective cohort study was conducted, recruiting 969 newborns in a third level hospital in Spain. The main maternal variables studied were: maternal age, parity, educational level, work occupation, smoking habit, gestational age, birth, weigh, feeding type, and duration of breastfeeding. All the participants were followed for a year to determinate the duration of breastfeeding and to know the reason of the abandonment. Results: At 6 months, the percentage of maternal lactation was cut in half and only 24.6% of these mothers maintain. Mainly 15.80% of the mothers decide to give up the exclusive maternal lactation of their own free desire, and 15.41% because they suspect hypogalactia. The work cause is the third reason of abandonment in both cases. Conclusions: Our results show the need to improve the health policies of promotion, protection and support the initiation of breastfeeding. In particular, our results show the importance of the work factor with particular emphasis on improving conciliation measures.

Parts I and II of this 3-part series indicated how a global review of both English-language and non-English language papers plus a focus on a lipidosterolic extract of Serenoa repens (LSESr) having a standardized fatty acid profile have together engendered new insights about the biological activity of LSESr vs. LUTS. In this last of a 3-part series, data from the world literature is presented that confirms that LSESr efficacy is the predominant finding in clinical trials. Despite two placebo-controlled clinical trials performed in the U.S. that failed to confirm a benefit of LSESr vs. placebo in LUTS, the global body of the peer-reviewed literature attests not only to efficacy but also to safety. Results will be presented of important trials that compare LSESr to alpha-blockers such as tamsulosin (Flomax®) as well as to 5α-reductase inhibitors such as finasteride (Proscar®) that demonstrate consistent findings of near equivalency between LSESr and these pharmacologic agents. Studies relating data indicative of an additive effect or synergy between LSESr and tamsulosin will be presented as well. The heightened effectiveness of LSESr in men with severe LUTS vs. moderate LUTS expands the importance of our scrutinization of the global literature concerning LSESr. Of great consequence are the contributions of non-English language peer-reviewed publications that have consistently provided evidence of LSESr efficacy in treating LUTS/BPH. These peer-reviewed articles have shown that the effect of LSESr is not that of a placebo. Finally, a comparison of the LSESr extraction products used in the treatment of LUTS, and a discussion of the milieu factors that affect the natural history of LUTS and influence the outcome of clinical trials complete this sedulous analysis of LSESr vs. LUTS.

Pure orbital blowout fractures occur within the confines of the internal orbital wall. Restoration of orbital form and volume is paramount to prevent functional and esthetic impairment. The anatomical peculiarity of the orbit has encouraged surgeons to develop implants with customized features to restore its architecture. This has resulted in worldwide clinical demand for patient-specific implants (PSIs) designed to fit precisely in the patient's unique anatomy. Fused filament fabrication (FFF) three-dimensional (3D) printing technology has enabled the fabrication of implant-grade polymers such as Polyetheretherketone (PEEK), paving the way for a more sophisticated generation of biomaterials. This study evaluates the FFF 3D printed PEEK orbital mesh customized implants with a metric considering the relevant design, biomechanical, and morphological parameters. The performance of the implants is studied as a function of varying thicknesses and porous design constructs through a finite element (FE) based computational model and a decision matrix based statistical approach. The maximum stress values achieved in our results predict the high durability of the implants, and the maximum deformation values were under one-tenth of a millimeter (mm) domain in all the implant profile configurations. The circular patterned implant (0.9 mm) had the best performance score. The study demonstrates that compounding multi-design computational analysis with 3D printing can be beneficial for the optimal restoration of the orbital floor.

Pulmonary embolism (PE) is one of the leading causes of cardiovascular mortality, therefore new parameters regarding risk stratification are sought after. In patients admitted for acute PE we investigated associations between the initial coagulation impairment, expressed by prothrombin time international normalised ratio (INR), and parameters reflecting PE severity. Furthermore, in-hospital, 30-day and long-term mortality were also evaluated. The analysis included 848 patients who were divided into two groups: with normal INR≤1.2, and elevated INR>1.2 (252 patients, 29.7%). The group with elevated INR presented higher incidence of tachycardia and lower systolic blood pressure, higher CRP, d-dimer, and NT-proBNP. This group presented higher estimated systolic pulmonary artery pressure (49 IQR39-62mmHg vs 43 IQR32-53mmHg, p<0.001) and shorter pulmonary artery acceleration time (65 IQR55-85ms vs 81 IQR63-102ms; p<0.001). Patients with elevated INR had more often a sPESI of 1 or higher (78%vs60%, p=0.003). Cox regression model revealed that age, leukocyte level, SBP, neoplasm, and INR are associated with higher risk of death (p<0.001). Finally, elevated INR was associated with higher in-hospital (13%vs3%; p<0.001), 30-day (19%vs6%; p<0.001), and long-term mortality (p<0.001). Summing up, elevated INR on admission is frequent in patients with PE, reflects worse clinical condition and is related to PE severity and prognosis.

Given the extent of this global analysis, this report will be presented in three sections. Part I will introduce LUTS. What are the demographics of LUTS? What symptoms are assessed by LUTS and how do we quantify LUTS? Why would a non-prescription item be a valuable consideration in LUTS treatment versus other treatment options? What is basic information about Serenoa repens and what defines a standardized LSESr product? What are the published trials that have affected the acceptability of Serenoa repens in the treatment of LUTS? Finally, a major portion of Part I will discuss the four major reviews of Serenoa repens versus LUTS that have influenced how it is accepted in the USA, in Europe, and other parts of the world. Part I, therefore, lays the groundwork and is foundational for the important findings relating to LUTS and Serenoa repens that will be presented in Parts II and III.

Part I of this 3-part series provided the groundwork for understanding the role of a standardized lipidosterolic extract of Serenoa repens (LSESr) in the treatment of LUTS. It documented that a treatment having a high therapeutic index (i.e., a ratio of benefit to adverse reactions) is a critical need in the demographic context of a rapidly growing elder population. Part I described the clinical symptomatology of LUTS and how it is quantified. A critique of the reports from four authoritative bodies: the European Scientific Cooperative on Phytotherapy (ESCOP), Cochrane 2012, the European Medicines Agency (EMA), and the AUA (American Urological Association) was presented. The foundation above then fine-tuned our search to require (a) consistent evaluability criteria, (b) the quantification of clinical findings, (c) the need to focus on studies employing a standardized LSESr product meeting the fatty acid profile set forth by the European Medicines Agency (EMA) and the US Pharmacopeia and (d) a global assessment of scientific investigations published in all languages and not limited to only English. Part II details the following “new” findings when LSESr vs. LUTS is examined with the above constraints.

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments are conducted according to clinical symptoms. Objective and biological validation are lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers in-cluding brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interfer-on-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.

Patients with lean NAFLD make up an increasing subset of liver diseases. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and nonlean patients. The study comprised 606 adults from the community, stratified into lean or nonlean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The OR of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72-3.98; P for trend<0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09-3.98; P for trend 0.026), while nonlean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

We performed a comprehensive analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin. We aimed to describe the genomic landscape of AS in a cohort of 143 cases of AS profiled by Caris Life Sciences. Data of Next Generation Sequencing (NGS) with a 592 gene panel was available for the entire cohort. Fifty-three cases had data of Whole Exome Sequencing (WES) which we used to study the microenvironment phenotype. Immuno-therapy (IO) response biomarkers: Tumor Mutation Burden (TMB), Microsatellite Instability (MSI) and PD-L1 status were included. IO-response markers were present in 36.4% of the cohort and in 65% of head and neck AS (H/N-AS) (p<0.0001). H/N-AS cases had predominantly muta-tions in TP53 (50.0%, p=0.0004), POT1 (40.5%, p<0.0001) and ARID1A (33.3%, p=0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p<0.0001), HRAS (16.1%, p=0.0377), and PI3KCA (16.1%, p=0.2352). A microenvironment with a high immune signature, associated with better response to IO, was present in 13% of the cases. This signature was evenly distributed among different primary sites. We found that the molecular biology for AS varies significantly according to the primary site. Our findings can facilitate the design and optimiza-tion of therapeutic strategies for AS to overcome resistance to IO and targeted therapies.

Purpose: To determine whether pre-surgical treatment using long-acting somatostatin analogues (SSAs) may improve surgical outcomes in acromegaly. Methods: Retrospective study of 48 patients with acromegaly operated by endoscopic transsphenoidal approach and for first time. Surgical remission was evaluated based on the 2010 criteria. Results: Most patients, 83.3% (n=40), harboured macroadenomas and 31.3% (n=15) invasive pitu-itary adenomas. Fourteen patients were treated with lanreotide LAR and 6 with octreotide LAR, median monthly doses of 97.5 [range 60-120] and 20 [range 20-30] mg, respectively, for at least 3 months preoperatively. Presurgical variables were comparable between pre-treated and un-treatred patients (P>0.05). Surgical remission was more frequent in those pre-treated with monthly doses ≥90 mg of lanre-otide or ≥30 mg of octreotide than in untreated or pre-treated with lower doses (OR=4.64, P=0.025). However, no differences were found between pre-treated and untreated patients when lower doses were included or between those treated for longer than 6 months compared to those untreated or pre-treated for shorter than 6 months. Similarly, no differences were found either in terms of surgical or endocrine complications (OR=0.65, P=0.570)), independently of the doses and the duration of SSA treatment (P>0.05). Conclusions: The dose of SSAs is a key factor during pre-surgical treatment, since the beneficial effects in surgical remission were observed with monthly doses equal or higher than 90 mg of lanreotide and 30 mg of octreotide, but not with lower doses.

Background: Spine shape parameters, such as leg length, kyphotic or lordotic angle, are influenced by low back pain. There is also evidence that the thoracolumbar fascia plays a role in such pa-thologies. This study examined the immediate effects of a myofascial release technique (MFR) on the thoracolumbar fascia and of an osteopathic treatment (OMT) on postural parameters in pa-tients with acute low back pain (aLBP). Methods: This study was a single-blind randomized pla-cebo-controlled trial. Seventy-one subjects (43.8 ± 10.5 years) suffering from aLBP were randomly and blinded assigned to three groups to be treated with MFR, OMT or a placebo intervention. Spinal shape parameters (functional leg length discrepancy (fLLD), kyphotic angle, lordotic an-gle) were measured before and after the intervention using video raster stereography. Results: Within the MFR group, fLLD reduced by 5.2 mm, p < 0.001 and kyphotic angle by 8.2 degrees, p < 0.001. Within the OMT group, fLLD reduced by 4.5 mm, p < 0.001 and kyphotic angle by 8.4 °, p = 0.007. Conclusion: MFR and OMT have an influence on fLLD and the kyphotic angle in aLBP patients. The interventions could have a regulating effect on the impaired neuromotor control of the lumbar muscles.

1) Background. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, characterized by extensive necrosis and detachment of the epidermis. 2) Case presentation. We present a case of a 46-year-old patient with late-stage high-grade serous ovarian cancer who was primarily treated with neoadjuvant chemotherapy and interval debulking which was followed by adjuvant chemotherapy. At first recurrence, she was again treated with chemotherapy and due to severe abdominal pain, an elastomeric pump containing analgesics, anti-inflammatories and ondansetron was administered. In the same month, she was admitted to the hospital due to severe dysphagia and in the following days, she developed haemorrhagic vesiculobullous lesions on facial skin and trunk. Stevens-Johnson syndrome was confirmed and ondansetron as a leading cause was discontinued. Despite multimodal treatment, her condition deteriorated, and she died. 3) Discussion and conclusion. Although gynaecologists rarely encounter Stevens-Johnson syndrome, high mortality of the disease should ensure a low threshold for diagnosing and treating this disease.

Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium in sites outside the uterus. Estimates of prevalence typically quote rates of ~10% of women of reproductive age, equating to ~190 million women world-wide. Three subtypes of endometriosis are usually considered when discussing the aetiology of the disorder - superficial peritoneal, ovarian (endometrioma cysts), and deep (infiltrating). Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome wide association studies (GWAS) have been conducted allowing unbiased scanning of the genome for single nucleotide polymorphisms (SNPs) in many thousands of individuals. These studies have identified SNPs that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). Amongst the larger scale GWAS there has been replication of SNPs near genes involved in oestrogen and other signalling pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. The results from patients with endometriosis have also provided an opportunity to make comparisons with GWAS conducted on other patient cohorts including those with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and conditions that are reported by women with endometriosis (migraine, depression). These comparative studies have highlighted some shared genetically-controlled biological mechanisms, including hormone-regulated pathways which might explain the co-occurrence of endometriosis with these disorders. In summary, unbiased genetic analysis has provided new insights into the genetic factors that may contribute to increased risk of developing endometriosis. New studies are needed to broaden the range of patients contributing to these datasets and to improve integration with non-genomic and tissue expression data before their full potential for diagnosis and improvements in patient care can be fully realised.

Background: Pneumococcal carriage surveillance study took place in urban and rural areas for Jordanian children in the period 2015-2019. Objectives: Determine urban and rural differences in pneumococcal carriage rate, resistance, and serotypes from healthy Jordanian children of Amman (urban) and eastern Madaba (rural). Methods: Nasopharyngeal swabs (NP) were taken from 682 children aged 1 to 163 months. Pneumococcal identification, serotyping and resistance were done according to standard method. Results: Number of cases tested for Amman 267 and for eastern Madaba 415. Carriage rate for eastern Madaba was 39.5% and for Amman 31.1%. Predominant serotypes for eastern Madaba and Amman were 19F (21.3%; 15.7%), 23F (12.2%; 9.6%), 14 (6.7%; 2.4%), 19A (4.9%; 2.4%), 6A (5.5%; 3.6%). Resistance rates for eastern Madaba and Amman were: penicillin (95.8%; 81.9%), clarithromycin (68.9%; 59.0%), clindamycin (40.8%; 31.3%), and trimethoprim-sulfamethoxazole (73.2%; 61.4%). Coverage of PCV7, PCV13, and the future PCV20 for Amman were 42.2%, 48.2%, and 60.2%; and for eastern Madaba were 50.0%, 62.2%, and 73.2%, respectively. In Amman 25.8% have received 1-3 PCV7 injections compared to 1.9% in eastern Madaba. Conclusions: There was significant differences in carriage, resistance and coverage in both regions. The potential inclusion of PCV vaccination program for rural areas is essential.

The treatment of viral infections is challenging owing to the intricate structure and metabolism of the viruses. In addition, they can highjack host cellular metabolism, mutate and adapt to harsh environmental conditions. The novel coronavirus (SARS-CoV-2) displays further resilient attributes, making its eradication even more difficult. SARS-CoV-2 is an enveloped virus whose replication can be targeted by limiting the substrates available for structural incorporation. One such molecule that limits substrate availability and has received much attention lately is 2-Deoxy-d-glucose (2-DG). SARS-CoV-2 infection induces glycolysis, impairs mitochondrial function, and damages the infected cells. Administration of 2-DG can inhibit increased glycolytic flux and some other metabolic processes to cause the cessation of viral replication. This article provides a review of the mechanism of action and safety concerns associated with administering 2-DG in the treatment of COVID-19. The drug can have adverse effects on normal cell metabolism since it targets cells non-selectively, possibly in a dose-dependent manner. In addition, the drug has limited use in SARS-CoV-2 infection associated with stroke, hypoxic-ischemic encephalopathy, and critical illness.

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 150 million individuals and killed 3 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccines development, COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

Background Although high-density lipoprotein has cardioprotective effects, the association between serum high-density lipoprotein cholesterol (HDL-C) and hypertension is poorly understood. Objective We investigated whether low and high concentrations of HDL-C are associated with hypertension using a large healthcare dataset. Methods In a community-based cross-sectional study of 1,493,152 Japanese people aged 40–74 years who underwent a health checkup, blood pressures and clinical parameters, including nine HDL-C concentrations (20–110 mg/dL or over) were investigated. Results A crude U-shaped relationship was observed between the nine HDL-C concentrations and blood pressure in males (n = 830,669), while a left-to-right inverted J-shaped relationship was observed in females(n = 662,483). An age-adjusted logistic regression analysis showed J-shaped relationships (left-to-right inversion in females) between HDL-C and odds ratios for hypertension (≥140/90 mmHg), with lower limits of 60–79 mg/dL in males and 90–99 mg/dL in females, which were unchanged after adjusting for smoking, habitual exercise, alcohol consumption, and pharmacotherapy for hypertension, dyslipidemia, and diabetes. However, further adjustment for body mass index and serum triglyceride concentration revealed latent positive linear associations between HDL-C and hypertension, although the association between extremely high HDL-C (≥100 mg/dL) and hypertension was attenuated in non-alcohol drinkers. Conclusion Both low and extremely high HDL-C concentrations are associated with hypertension. The former association may be dependent on excess fat mass, which is often concomitant with low HDL-C, whereas the latter association may be dependent on frequent alcohol consumption.

Breast cancer, although the most frequently diagnosed malignant tumour in humans, has a less clear aetiology compared to other frequent cancer types. Mouse-mammary tumour virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the aetiology of some breast cancers in humans, since it has been identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world population. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional centre from Romania. We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. Since none of the examined samples was positive for MMTV-like target sequences on PCR we could not prove that MMTV plays a role in the aetiology of breast cancer in our patient group. This finding is similar to publications of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe (including Romania) and some parts of Asia.

Objectives: Robotic bilateral axillary breast approach (BABA) thyroid surgery began in 2008 and is now one of the most widely used remote-access thyroid surgeries worldwide. This study aimed to analyze the results of 500 robotic BABA thyroid surgeries performed in a single institution in Korea compared with open thyroid surgery. Methods: From December 2018 to March 2020, 502 robotic BABA thyroidectomies (RTs) and 531 conventional open thyroidectomies (OTs) were performed in our institution by a single endocrine surgeon. We retrospectively reviewed patient medical records and performed a comparative analysis of OT and RT. Results: The RT group was younger (43.41±11.41 versus 54.28±13.41 years, p<0.001) and had a higher proportion of females (84.3% versus 69.3%, p<0.001), a lower BMI (24.66±3.97 versus 25.83±4.07 kg/m2), a higher proportion of lobectomies (52.6% versus 45.2%) and a lower proportion of lateral neck dissections (3.4% versus 10.0%, p<0.001). The RT group had a lnger operation time (145.33±40.80 versus 93.39±43.55 minutes, p<0.001) and higher surgical cost. Although the OT group had a larger tumor size and higher proportion of extrathyroidal extension, the numbers of retrieved lymph nodes were not significantly different between the two groups. Additionally, there was no difference in the stimulated thyroglobulin level before radioactive iodine therapy (7.01±35.73 versus 8.39±58.77, p=0.782). The rates of transient vocal cord palsy and transient hypoparathyroidism were significantly lower in the RT group, and those of scar-related complications were higher in the OT group. Conclusion: Robotic BABA thyroid surgery has advantages not only in better cosmetic outcomes but also in lower rates of vocal cord palsy and hypoparathyroidism, with comparable lymph node retrieval and serum thyroglobulin levels.

Introduction: During mixed dentition period, the growth and development process of dentocraniofacial complex occurs, with temporomandibular joint as one of its centers of growth. The condition of temporomandibular joint can be seen from its condylar head shape; therefore, it is essential to understand the normal morphology of condylar head during mixed dentition period. Objective: this research aims to view the general morphology of condylar head during mixed dentition period. Method: Samples of panoramic radiographs were collected from Ma-ranatha Dental Hospital, Bandung, Indonesia. It consists of 70 male and 70 female subjects, di-vided into three groups according to their phase of mixed dentition period. Shape of subjects' condylar heads was determined by analyzing and comparing the tracing results of condyle in panoramic radiograph. Result: Study showed in first transitional period of mixed dentition, condylar head shape is dominated by round, as growth and development go on, the domination of condylar head shape is changed into convex on second transitional period. Conclusion: Mostly condylar head shape morphology during mixed dentition period is round-headed in first transitional and inter-transitional period, and convex-headed in second transitional period.

(1) Background: Benefits and timing of percutaneous dilatational tracheostomy (PDT) in Intensive Care Unit (ICU) COVID-19 patients are still controversial. PDT is considered a high risk procedure for transmission of SARS CoV-2 to health care workers (HCWs). The present study analyzed optimal timing of PDT, clinical outcomes of patients undergoing PDT and safety of HCWs performing PDT. (2) Methods: 133 COVID-19 patients underwent PDT in our ICU from April 1, 2020 to March 31, 2021, 23 patients were excluded and 110 patients were enrolled. A trained medical team was dedicated to the PDT procedure. Demographic, clinical history and outcome data were collected. Patients who underwent PDT were stratified into two groups: early group, PDT ≤ 12 days from orotracheal-intubation (OTI) and late group, &gt;12 days from OTI; HCW surveillance program was performed. (3) Results: Early group included 57 patients and late group included 53 patients. Early group patients showed shorter ICU length of stay and fewer days of mechanical ventilation than the late group (p&lt;0.001). At day 7 after tracheostomy, early group patients required fewer intravenous anesthetic drugs and experienced an improvement of ventilation parameters, PaO2/FiO2-Ratio, PEEP and FiO2 (p&lt;0.001). No difference in case fatality ratio between the two groups was reported. No SARS-CoV-2 infection was reported in HCWs performing PDT. (4) Conclusions: PDT was safe and effective for COVID-19 patients, since it improved respiratory support parameters, reduced ICU length of stay and duration of mechanical ventilation, and optimized the weaning process. The procedure was safe for all HCWs involved in the dedicated medical team. The development of standardized early PDT protocols should be implemented and PDT procedure could be considered as first line approach in ICU COVID-19 requiring prolonged mechanical ventilation.

Despite the many advantages of lung ultrasound (LUS) in the diagnosis and management of patients with dyspnea, adoption among hospitalists has been slow. We performed semi-structured interviews of hospitalists from 4 diverse health systems in the US to understand determinants of adoption within a range of clinical settings. We used the Diffusion of Innovation Theory to guide a framework analysis of the data. Of 27 hospitalists invited, we performed in-terviews of 22 from 4 hospitals of diverse types. Median years post-residency of interviewees was 10.5 [IQR:5-15]. Four main themes emerged: 1) There are important clinical advantages to LUS despite operator dependence, 2) LUS enhances patient and clinician experience, 3) Investment of clinician time to learn and perform LUS is a barrier to adoption but yields improved efficiency for the health system and 4) Mandated training and use may be necessary to achieve broad adoption as monetary incentives are less effective. Despite perceived benefits of LUS for patients, clinicians and health systems, an important barrier to broad LUS adoption is the experience of time scarcity by hospitalists. Future implementation strategies should focus on changes to the clinical environment that address clinician barriers to learning and adoption of new skills.

Rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to 9-tetrahydrocannabinol (9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that 9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg 9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to 9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, 9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACC, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, was also observed in these 9-THC-exposed offspring. Collectively, these findings indicate that prenatal 9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Most hair relaxers or straighteners used for Afro-textured hair have a pH above 11. This pH, according to international occupational health and safety guidelines, is corrosive to the skin. Further, relaxers are associated with a 3-6 times increased risk of alopecia. The skin also gets into contact with these hair straightening products during application resulting in skin irritation. Using animals as test subjects to determine these products' potential risk and safety margin is standard practice; however, with the European Union (EU) ban on animal testing, the testing method needs to be replaced by newer in vitro laboratory technologies. This study used previously and newly established in vitro cell-based technologies and human-skin derived cells as laboratory models to evaluate relaxer-induced cytotoxicity. These technologies include endpoint (MTT, CCK-8 and flow cytometry) and real-time assays (real-time cell analysis (RTCA) and extracellular flux analysis). Cellular toxicity was evident following treatment of keratinocytes and fibroblasts with acceptable concentrations of thioglycolic acid (TGA, HSCH2COOH), ammonium bisulphite (NH4HSO3), lithium hydroxide (LiOH) and sodium hydroxide (NaOH) based relaxers. Real-time assays showed significant reductions (P<0.001) in cell index and ATP production following treatment of keratinocytes with as little as one-tenth of the acceptable concentrations. Increased apoptosis (47.9%, 58.0%, 76.7% and 80.3%) also occurred in cells after treatment with TGA, NH4HSO3, NaOH and LiOH, respectively. In conclusion, this study demonstrated that using skin cells in conjunction with advanced cell-based technologies could serve as alternatives to laboratory animals for accessing the toxicity margin of hair relaxers, straighteners and other cosmetics.

Background: Adolescence is a developmental stage when there is a high risk of engaging in non-suicidal self-injury (NSSI). There is recent interest in the study of thwarted belongingness and perceived burdensome as variables associated with the frequency of NSSI in adolescents. Meaning in life (MIL) could be negatively associated with thwarted belongingness and perceived burdensome. To date, no studies have analyzed whether thwarted belongingness and perceived burdensomeness could be associated with the frequency of NSSI in adolescents. On the other hand, no studies have analyzed the buffering role of MIL in the association between thwarted belongingness and perceived burdensomeness and the frequency of NSSI. Aims: a) to test whether thwarted belongingness and perceived burdensomeness are associated with NSSI frequency; b) to test whether MIL moderates the association between thwarted belongingness and NSSI frequency; and c) to test whether MIL moderates the association between perceived burdensomeness and NSSI frequency. Method: The sample consisted of N = 1531 participants between 12 and 18 years old from Spain. The participants filled out the Inventory of Statements about Self-Injury, Purpose-In-Life Test-Adolescents Version, and Interpersonal Needs Questionnaire. Moderation analysis were performed. Results: Thwarted belongingness and perceived burdensomeness were positively associated with the frequency of NSSI in Spanish adolescents. MIL was a moderating variable between thwarted belongingness and the frequency of NSSI, and between perceived burdensomeness and the frequency of NSSI. Conclusion: Thwarted belongingness and perceived burdensomeness could be a risk factor for NSSI and MIL could be a protective factor against NSSI, and adding these variables to current descriptive theories of NSSI in adolescents would allow us to improve the assessment and treatment protocols for adolescents with NSSI.

Overt hyperthyroidism during pregnancy is associated with risk of maternal-fetal complications. The antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal–neonatal hy-pothyroidism. This study evaluated ATD treatment and thyroid function control during preg-nancy, and pregnancy outcome in women with hyperthyroidism. Patients and methods: retro-spective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with hyperthyroidism diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. Results: 26 women had Graves’ disease (GD, 33 pregnan-cies), 1 had a hyperfunctioning autonomous nodule, 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical hyperthyroidism, 5 euthyroid with previous GD remission before conception). One spontaneous abortion at 5 weeks (3.4% of pregnancies) and 1 premature delivery at 32 weeks with perinatal death in 24h (3.4%) were recorded in 2 of the 8 pregnancies of GD patients diagnosed shortly before (< 6 weeks) or during gestation. In women treated more than 6 months until conception (20 pregnancies): a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; b) ATD was withdrawn in 40% of pregnancies in trimester (T) I, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in TIII; c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T I, II and III respectively; FT4 was increased in 5.8% (T I) and sub-normal in 11.75% in TII and III; d) one fetal death due to a true umbilical cord knot was recorded. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). One child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). Mean birth weight did not differ from that of the control group. Conclusion. In hyperthyroid women with long-term ATD control before con-ception, drugs could be withdrawn in TI in a third of them, and fetal complications were rare. Frequent serum TSH and FT4 monitoring is needed in order to maintain optimal thyroid function during pregnancy.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma is possibly derived from nodal T-cell/histiocyte-rich large B-cell lymphoma; however, a transition between the nodal and splenic micronodular forms has not been described to date. Of note, the only lymph nodes to be involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes, and that, with partial involvement only. Kan et al, in their series of articles, have raised the possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations (apoptosis, necrosis, tissue shrinkage), which modify or even obscure the diagnostic morphological features. The indications for glucocorticoid therapy are either related to the suspected lymphoma, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic, rather than nodal subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved tissue, causing disparate morphologies in the spleen. Apoptosis, as induced by corticosteroids, is hypothesized as the major mechanism initiating the histopa-thological and functional changes in the splenic micronodular variant of our patients.

Osteoarthritis and rheumatoid arthritis are two of the most common chronic inflammatory joint diseases, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. The pathology of both osteoarthritis and rheumatoid arthritis involves multiple tissues within the joint, including the synovial joint lining and the bone, as well as the articular cartilage in osteoarthritis. In this review, we discuss the potential for the development of oligonucleotide therapies for these disorders by examining the evidence that oligonucleotides can modulate the key cellular pathways that drive the pathology of the inflammatory diseased joint pathology as well as evidence in preclinical in vivo models that oligonucleotides can modify disease progression.

Psychedelics extracted by plants have been used in religious, spiritual and mystic practices for millennia. In 1957, Dr. Hofmann have identified and synthesized the prodrug psilocybin, a substance present in more than 200 species of psychedelic mushrooms. Although the limitations related to the scientific design of many studies, clinical observations performed during the 1950s and the 1960s have shown a potential therapeutic effect of psilocybin in patients affected by depressive symptoms, anxiety, and conversion disorder. Psilocybin was classed as a schedule I substance in 1970, but the fascination for psychedelics remained almost unchanged over time promoting a new scientific interest starting from the 1990s. Recent studies provided further evidences supporting the suggestive hypothesis of a therapeutic use of psilocybin for treating various psychiatric disorders including: pathological anxiety, mood depressive disorder and addiction.

Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.

Lymph nodes are secondary lymphoid organs that appear as bean-like nodules usually <1 cm in size, and they are localized throughout the body. Many antigen-presenting cells such as dendritic cells and macrophages reside in lymph nodes, where they mediate host defense responses against pathogens such as viruses and bacteria. In cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs) to react to cancer cell–derived antigens. Macrophages located in the lymph node sinus are of particular interest in relation to anti-cancer immune responses because many studies using both human specimens and animal models have suggested that lymph node macrophages play a key role in activating anti-cancer CTLs. The regulation of lymph node macrophages therefore represents a potentially promising novel approach in anti-cancer therapy.

Low back pain (LBP) is a leading cause of disability. It significantly impacts the patient’s quality of life, limits their daily living activities, and reduces work productivity. To reduce the burden of LBP, several pharmacological and non-pharmacological treatment options are available. This review summarizes the role of heat therapy in the management of LBP. First, we outline the common causes of LBP, then discuss the general mechanisms of heat therapy on (LB)P, and finally review the published evidence regarding the impact of heat therapy in patients with acute or chronic non-specific LBP. This review demonstrates that continuous, low-level heat therapy provides pain relief, improves muscular strength, and increases flexibility. Therefore, this effective, safe, easy-to-use, and cost-effective non-pharmacological pain relief option is still relevant in modern clinical practice.

It was the aim of this study to provide a more precise timeframe of development of the gonads and genital ducts in the equine fetus around the time of sexual differentiation. This included the identification and localisation of the primordial germ cell population. Equine fetuses between 45 and 60 days of gestation were evaluated using a combination of micro-computed tomography scanning, immunohistochemistry, and multiplex immunofluorescence. Fetal gonads increased in size by 23-fold from 45 to 60 days of gestation, paralleled by a greater increase in metanephros volume. Signs of mesonephros atrophy were detected during this time. Tubular structures of the fetal testes were present from day 50 onwards, whereas cell clusters dominated in the fetal ovary. The genital ducts were well-differentiated and presented a lumen in all samples. No sign of mesonephric or paramesonephric duct degeneration was detected. Expression of AMH was strong in the fetal testes but absent in ovaries. Irrespective of sex, primordial germ cells selectively expressed LIN28. Migration of primordial germ cells from the mesonephros to the gonad was detected at 45 days, but not at 60 days of development. Their number and distribution within the gonad were influenced (p&lt;0.05) by fetal sex. Most primordial germ cells (86.8 ± 3.2% in females and 84.6 ± 4.7% in males) were characterized as pluripotent according to co-localization with CD117. However, only a very small percentage of primordial germ cells was proliferating (7.5 ± 1.7% in females and 3.2 ± 1.2% in males) based on co-localization with Ki67. It can be concluded that gonadal sexual differentiation in the horse occurs asynchronously with regard to sex but already before 45 days of gestation.

Tissue Doppler Imaging (TDI) is a non-invasive, echocardiographic imaging technique that measures myocardial motion velocity throughout the cardiac cycle using Doppler principles. While conventional Doppler techniques assess blood flow velocity by sensing high-frequency, low amplitude signals from small, fast-moving blood cells, TDI uses the same Doppler principles to instead measure high-amplitude, lower-velocity signals of myocardial tissue. Methods A literature review was conducted to survey and review studies investigating the limitations, strengths, physical principles, novel methods, applications in diseased states, and prognostic capabilities of TDI. These articles were further screened for inclusion, and those deemed ineligible or irrelevant to the scope of the review were discarded. In total, 19 studies were included in the qualitative synthesis. Results TDI is shown to be an effective method for detailed quantification of cardiac function. It provides an early means of diagnosing cardiac dysfunction and is a valid prognostic indicator for various forms of heart disease. TDI's versatility and precision allows clinicians to predict the clinical course of disease, leading to early intervention and the selection of targeted care management plans for many cardiac pathologies. Despite imaging limitations like angle dependence and incapacity for passive and active motion differentiation, further investigation continues to reveal novel TDI methodologies that advance the scope of this imaging technique.

The urgent need for effective, safe and equitably accessible vaccines to tackle the ongoing spread of COVID-19 led researchers to generate vaccine candidates targeting varieties of immunogens of SARS-CoV-2. Because of its crucial role in mediating binding and entry to host cell and its proven safety profile, the subunit 1 (S1) of the spike protein represents an attractive immunogen for vaccine development. Here, we developed and assessed the immunogenicity of a DNA vaccine encoding the SARS-CoV-2 S1. Following in vitro confirmation and characterization, the humoral and cellular immune responses of our vaccine candidate (pVAX-S1) was evaluated in BALB/c mice using two different doses, 25 µg and 50 µg. Our data showed high levels of SARS-CoV-2 specific IgG and neutralizing antibodies in mice immunized with three doses of pVAX-S1. Analysis of the induced IgG subclasses showed a Th1-polarized immune response as demonstrated by the significant elevation of spike-specific IgG2a and IgG2b compared to IgG1. Furthermore, we found that immunization of mice with three doses of 50 µg of pVAX-S1 could elicit significant memory CD4+ and CD8+ T cell responses. Taken together, our data indicates that pVAX-S1 is immunogenic and safe in mice and is worthy of further preclinical and clinical evaluation.

3,4-methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the “bath salts”. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigm. We also assessed the effects of the combination of CBD, and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Additionally, CBD exerted anxiolytic-like effects, but only in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice vary depending on the requirements of the learning task, resulting in a complex response. More research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.

The study aimed to evaluate the association between the changes in ventilatory variables (tidal volume (Vt), respiratory rate (RR), and lung ventilation (VE)) and deoxygenation of m.intescostales (∆SmO2-m.intercostales) during a maximal incremental exercise in nineteen male competitive marathon runners. The ventilatory variables and oxygen-consumption (VO2) were recorded breath-by-breath by exhaled gas analysis. A near-infrared spectroscopy device (MOXY) located in the right-hemithorax allowed recording SmO2-m.intercostales. To explore changes in oxygen levels in muscles with high demand during exercise, a second MOXY records SmO2-m.vastus laterallis. The triphasic model of exercise intensity was used for evaluating changes in SmO2 in both muscle groups. We found that ∆SmO2-m.intercostales correlated with VO2-peak (r=0.65; p=0.002) and the increase of VE (r=0.78; p=0.001), RR (r=0.54; p=0.001), but not Vt (p=0.210). The interaction of factors (muscles X exercise-phases) in SmO2 expressed as an arbitrary unit (a.u) was significant (p=0.005). At VT1 were no difference (p=0.177), but SmO2-m.intercostales was higher at VT1 (p&lt;0.001) and VO2-peak (p&lt;0.001). In competitive marathon runners, the m.intercostales deoxygenation during incremental exercise is directly associated with the aerobic capacity and increased lung ventilation and respiratory rate, but not tidal volume. Besides, it shows less deoxygenation than m.vastus laterallis at intensities above the aerobic ventilatory threshold.

Abstract: As a risk factor, obesity is a threat to human well-being and related metabolic disorders such as diabetes mellitus and dyslipidemia. adipogenesis is defined as the proliferation and maturation of adipocyte predecessor cells to adipocyte. As the adipogenesis process decides adipocyte production, it may be considered a therapeutic target for obesity and obesity-related disorders. White adipose tissue abnormal expansion increases the size and number of adipocytes. For that reason, this review aims to spot the molecular mechanisms implicated in adipogenesis that lead to application in the therapeutic targets. Keywords: adipogenesis, signaling pathways, anti-obesity treatment, obesity

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease, for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKIs became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon re-treatment, indicating TKI discontinuation is safe. However, there is still a gap in the understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it ex-amines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

More research, including a randomized controlled trial, is needed to further investigate the the combined treatment and gain better understanding of the treatment mechanisms.

The impact of sex in the development of long-term toxicities affecting the quality of life of cancer survivors has not been investigated experimentally. To address this issue, a series of neurologic and cardiologic endpoints were used to investigate sex-based differences triggered by paclitaxel treatment and radiotherapy exposure. Male and female WT mice were treated with Paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Cohorts were analyzed for behavioral and neurobiologic endpoints to assess systemic toxicity of paclitaxel or cardiovascular endpoints to assess radiotherapy toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice regardless of the treatment regimen. To provide insight into the possible sex-specific protective mechanisms, rhoB deficient animals and elderly mice (22 months) were used with a focus on the possible contribution of sex hormones including estrogen. RhoB deficiency and advanced age had no impact on neurocognitive impairment induced by Paclitaxel but reversed the cardioprotection was observed in females after radiotherapy. Conversely, rhoB deficiency protected males from radiation toxicity. In sum, rhoB was identified as a molecular determinant driving estrogen dependent cardioprotection in female mice, whereas neuroprotection was not sex-hormone dependent. To our knowledge, this study revealed for the first time sex- and organ-specific responses to paclitaxel and radiotherapy.

Background: Brachial-ankle pulse wave velocity (baPWV) is widely used as a marker of arterial stiffness. It has been suggested as a simple method for detecting arterial loads that can trigger left ventricular hypertrophy in the heart. Increased left ventricular hypertrophy in hypertensive patients is a predictor that will have an impact on increasing morbidity and mortality. Objective: This study aimed to evaluate the correlation between the baPWV and the left ventricular mass index (LVMI) in hypertensive patients. Methods: This cross-sectional study was conducted by collecting secondary data from hypertensive patients at the Heart Outpatient Clinic, with inclusion: aged more than 40 years old, suffering hypertension more than one year, and had baPWV and echocardiography data. Correlation between baPWV and LVMI was evaluated using the Pearson correlation test. Results: A total of 40 hypertensive patients were enrolled in this study. 60% were women. The mean age was 52.92 ± 9.50 years. Mean LVMI was 107.20 + 21.01 gram/m2. LVMI showed a significant association with age and systolic blood pressure (p=0.001 and 0.019, respectively). Mean baPWV was 1832.90 + 336.22 cm/sec. A significant association was found between baPWV and age and systolic blood pressure (p=0.000 and 0.049, respectively). There was a significant positive correlation between baPWV and LVMI (r=0.493, p=0.001); and between baPWV and Relative Wall Thickness (RWT) (r=0.404, p=0.01). Conclusion: This study shows that elevated baPWV is an indicator of increased LVMI in hypertensive patients. Examination of baPWV should be carried out routinely to detect earlier arterial stiffness as a morbidity and mortality prevention strategy in hypertensive patients.

Novel strategies have been developed to reduce or to avoid the intravitreal injections (IVTs) of the antiangiogenic (ranibizumab; RBZ) and the anti-inflammatory (triamcinolone acetonide; TA) agents used to treat vitreoretinal diseases. One of the strategies include liposomes. In this study, it was evaluated the safety and efficacy of topical triamcinolone-loaded liposomes formulation (TALF) as an adjuvant to intravitreal RBZ therapy in treatment-naive patients with neovascular age related macular degeneration (nAMD). Subjects were randomly assigned to the RBZ-TALF or the RBZ-pro re nata (RBZ-PRN) group. Patients from the RBZ-TALF group were instructed to apply TALF for a 12-month period after a single dose of RBZ. Patients from the RBZ-PRN group received three monthly RBZ-IVTs. Retreatment with RBZ was considered in case of nAMD reactivation. Related to safety, non-ocular abnormalities were observed during TALF therapy. Owing to the efficacy, non-significant differences are identified in visual acuity or central foveal thickness when the RBZ-PRN and RBZ-TALF groups are compared. Importantly the average number of RBZ injections was significantly lower in the RBZ-TALF group (2.5 ± 1.4 vs 6.1 ± 1.3 IVTs; p=0004). Therefore, TALF used as an adjuvant to RBZ reduce the number of RBZ-IVTs retreatment with optimal visual and anatomic results.

Background: In Transcranial Direct Current Stimulation (tDCS) the injected current gets distributed across the brain areas. The motive is to stimulate the target region-of-interest (ROI), while minimizing the current in non-target ROIs. For this purpose, determining the appropriate current-dose for an individual is difficult. Aim: To introduce Dose-Target-Determination-Index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current-dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of average current density at target ROI to the ROI with maximum value (peak region). Ideally target ROI should be the peak region, so DTDI shall range from 0 to 1. Higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups- (a) Young adults (20 ≥ x ˂ 40 years), (b) Mid adults (40 ≥ x ˂ 60 years), and (c) Older adults (60 ≥ x ˂ 80 years). DTDI’s were evaluated for the frontal montage with electrodes at F3 and right supra-orbital for three current doses 1mA, 2mA, and 3mA with the target ROI at left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals. The focality decreases with age and the decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. DTDI recommended dose should be prioritised based on the age (> 40 years) and sex (especially males) of an individual. The toolbox i-SATA(MNI) is freely available.

Atopic dermatitis (AD) is common inflammatory dermatosis, typically with chronic and recurrent course, which significantly reduces the quality of life. Sleep disturbances are considered to be remarkably burdensome ailments in the patients with AD, and are routinely included during assessment of disease severity. Therefore, endogenous substances engaged in the control of circadian rhythms might be important in pathogenesis of AD and, possibly, be used as biomarkers of disease severity or even in development of novel therapies. Melatonin (MT), the indoleamine produced by pineal gland (but also by multiple other tissues, including skin), plays a pivotal role in maintaining the sleep/wake homeostasis. Additionally, it possess strong antioxidant and anti-inflammatory properties, which might directly link chronic skin inflammation and sleep abnormalities characteristic of AD. The objective of this work is to systematically present and summarize the results of studies (both experimental and clinical) that investigated the role of MT in the AD, with focus on the antioxidant and immunomodulatory effects of MT.

A face serum composed of a combination of biologically active compounds was evaluated for safety and efficacy in vitro, in a repeat insult patch test and in a human clinical efficacy trial. The serum inhibited tyrosinase activity modestly, decreased collagenase activity and exhibited notable free radical scavenging activity in vitro. It is gentle to the skin, as the serum did not irritate the skin or produce symptoms of allergic contact dermatitis in the 55 healthy adults that participated in the repeat insult patch test. In the efficacy trial, daily application of the face serum for 30 days significantly increased skin hydration, with all 35 volunteers experiencing improvement. Substantial improvements in skin elasticity, roughness (fine lines and wrinkles), and brightness also occurred during the trial. Dermatological examination also revealed a trend for reduced comedone count with use of the serum. Self-assessment responses revealed that all volunteers experienced improvements in multiple skin quality parameters and that participant perceptions are consistent with the results of the instrumental analyses. These findings indicated that the measured improvements in skin quality are not only statistically significant but are also clinically relevant as they were great enough for users of the face serum to feel and recognize.

Cystathionine gamma-lyase (CSE) is an essential Hydrogen sulphide (H2S)-producing enzyme that regulates diverse processes related to cardiovascular function. It is crucial to understand how exogenous H2S regulates CSE expression in vascular endothelial cells during hypoxia. We examined the regulatory effect of 100 μM H2S on the transcription and expression of CSE in HUVECs during hypoxia by luciferase assay, Western blotting, and quantitative RT-qPCR. Exogenous H2S influenced the promoter activity of CSE in HUVECs during hypoxia. Compared with 0 μM H2S, 100 μM H2S decreased the mRNA expression of CSE in HUVECs. Compared with 0 μM H2S, 100 μM H2S decreased the protein expression of CSE in HUVECs after 2 h of hypoxia. These findings suggest that vascular endothelial cells can respond to changes in H2S concentration in the blood during hypoxia.

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, and mechanistic studies of virus infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses, and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

Purpose: Nycthemeral (24-hour) glaucoma inpatient intraocular pressure (IOP) monitoring has been used in Europe for more than 100 years to detect peaks missed during regular office hours. Data supporting this practice is lacking, partially because it is difficult to correlate manually drawn IOP curves to objective glaucoma progression. To address this, we deployed automated IOP data extraction tools and tested for a correlation to a progressive retinal nerve fiber layer loss on spectral-domain optical coherence tomography (SDOCT). Methods: We created and deployed a machine-learning image analysis software to extract IOP data from hand-drawn, nycthemeral IOP curves of 225 retrospectively identified glaucoma patients. The relationship between demographic parameters, IOP and mean ocular perfusion pressure (MOPP) data to SDOCT data was analyzed. Sensitivities and specificities for the historical cut-off values of 15 mmHg and 22 mmHg in detecting glaucoma progression were calculated. Results: IOP data could be extracted efficiently. The IOP average was 15.2±4.0 mmHg, nycthemeral IOP variation was 6.9±4.2 mmHg, and MOPP was 59.1±8.9 mmHg. Peak IOP occurred at 10 AM and trough at 9 PM. Disease progression occurred mainly in the temporal-superior and -inferior SDOCT sectors. No correlation could be established between demographic, IOP, or MOPP parameters and SDOCT disease progression. The sensitivity and specificity of both cut-off points (15 and 22 mmHg) were insufficient to be clinically useful. Outpatient IOPs were non-inferior to nycthemeral IOPs. Conclusion: IOP data obtained during a single visit make for a poor diagnostic tool, no matter whether obtained using nycthemeral measurements or during outpatient hours.

(1)Background: This report was an effective evaluation of using multimedia educational program for self-care and quality of life in patients with a stoma at postoperative and established a simple threshold for enterostomy self-care skills.(2)Methods:108 patients with enterostomy were randomly assigned to receive either the intervention multimedia education program (including information about preparation for enterostomy care, cleaning method, manual bag replacement steps and precautions). The primary outcome was self-care ability and quality of life (defined as overall enterostomy self-care ability and overall quality of life), which was assessed at 2 weeks after intervention via an interview.(3)Results: Compared with those who in the conventional stoma education program, patients received the multimedia education program significantly improved their overall self-care ability and quality of life in statistically. The threshold of the enterostomy self-care skill scale was 20 points, and its corresponding sensitivity was 77.8%, and the specificity was 75.7%.(4)Conclusions: According to our study, the multimedia education program could enhance self-care ability of home care and quality of life in patients with enterostomy.

Subchondral bone loss is an important pathological feature of early-stage temporomandibular joint (TMJ) osteoarthritis (OA). Previous studies focused mainly on the bone resorption by osteoclasts in early-stage OA, but the bone formation feature has not drawn enough attention. Sema4D/Plexin-B1 is a pair of molecules expressed by osteoclast/osteoblast, which is capable of inhibiting bone formation by osteoblasts. The present study found that subchondral bone loss in early-stage TMJ OA was accompanied by up-regulated expression of Sema4D in cartilage and subchondral bone and Plexin-B1 in subchondral bone. Reducing Sema4D level could inhibit the subchondral bone loss and cartilage degeneration of early-stage TMJ OA. In vitro, results revealed that Sema4D could reduce the expression of osteocalcin (OCN) and alkaline phosphatase (ALP), and increase the migrating capability of Plexin-B1-positive osteoblasts. Our results revealed that elevated Sema4D expression in early-stage TMJ OA might decrease the bone formation activity of osteoblasts in the subchondral bone by binding to Plexin-B1 expressed by osteoblasts. Inhibiting Sema4D/Plexin-B1 signaling in the early-stage OA holds promise as a strategy for new therapeutic approaches to osteoarthritis.

The visual system is regulated by the nervous through neurotransmitters, which play an important role in visual and ocular functions. One of those neurotransmitters is acetylcholine, a key molecule that plays a diversity of biological functions. On the other hand, acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, is implicated in cholinergic function. However, several studies showed that in addition to their enzymatic functions, Acetylcholinesterase exerts non-catalytic functions. In recent years, the importance of evaluating all possible functions of acetylcholine-acetylcholinesterase has been evidenced. Nevertheless, there is evidence that suggests cholinesterase activity in the eye can regulate some biological events both in structures of the anterior and posterior segment of the eye and therefore in the visual information that is processed in the visual cortex. Hence, the evaluation of cholinesterase activity could be a possible marker of alterations in cholinergic activity not only in ocular disease but also in systemic diseases.

Objectives: To explore the potential of Radiomics alone and in combination with diffusion-weighted derived quantitative parameter namely apparent diffusion co-efficient (ADC) using supervised classification algorithms in predicting outcomes and prognosis. Materials and Methods: Retrospective evaluation of the imaging was done for a study cohort of uterine cervical cancer, candidates for radical treatment with chemo radiation. ADC values were calculated from the darkest part of the tumor, both before (labeled preADC) and post treatment (labeled postADC) with chemo radiation. Post extraction of 851 Radiomics features and feature selection by taking the union of the features which had Pearson correlation >0.35 for recurrence, >0.49 for lymph node and >0.40 for metastasis, analysis was done to predict clinical outcomes. Results: The study enrolled 52 patients who presented with variable FIGO stages and age range 28–79 (Median = 53 years) with median follow-up of 26.5 months (range, 7–76 months). Disease recurrence occurred in 12 patients (23%). Metastasis occurred in 15 patients (28%). A model generated with 24 radiomics features and preADC using a monotone multi-layer perceptron neural network to predict the recurrence yields AUC of 0.80 and kappa value as 0.55 and shows that addition of radiomics features on ADC values improves the statistical metrics by 40% approximately for AUC and 223% approximately for Kappa. Similarly, neural network model for prediction of metastasis re-turns AUC of 0.84 and kappa value as 0.65 over performs by 25% for AUC and 140% for Kappa approximately. There was a significant input of GLSZM features (SALGLE and LGLZE) and GLDM features (SDLGLE and DE) correlation with clinical outcomes of recurrence and metastasis. Conclusions: The study is an effort to bridge the unmet need of translational predictive biomarkers in stratification of uterine cervical cancer patients based on prognosis.

COVID-19 pandemic put pregnant women in high risk, but behavioural changes has also led to lower rates of preterm births in high-income countries. The main goal in this article is to study the impact that COVID-19 pandemic is having on pregnancy control and outcomes. This is a joint analysis of two cohorts. A pre-pandemic one includes 969 pregnant women recruited in 2018. The pandemic cohort comprises 1168 pregnant women recruited in 2020. Information on demographic and socio-economic characteristics, reproductive history, characteristics of the current pregnancy and its outcome were obtained from medical records. Caesarean section was more frequent in the pre-pandemic cohort (24% vs. 18%, p = 0.004). Birth with less than 37 weeks of gestational age was more frequent in the pre-pandemic cohort (6% vs. 5%, p = 0.04). Weight at birth lower than 2500 grams occurred more frequently in the pre-pandemic cohort (9% vs. 6%, p = 0.001). Exclusive breastfeeding at hospital discharge was more frequent in the pandemic cohort than in the pre-pandemic one (60% vs. 54%, p = 0.005). We are reporting reductions in Caesarean section and preterm birth during the pandemic in a hospital located Northern of Spain. Further analysis would clarify if these lessening are related to changes in health-related behaviour or health-care functioning.

The novel coronavirus disease (COVID-19) has created immense threats to public health on various levels around the globe. The unpredictable outbreak of this disease and the pandemic situation are causing severe depression, anxiety and other mental as physical health related problems among the human beings. To combat against this disease, vaccination is essential as it will boost the immune system of human beings while being in the contact with the infected people. The vaccination process is thus necessary to confront the outbreak of COVID-19. This deadly disease has put social, economic condition of the entire world into an enormous challenge. The worldwide vaccination progress should be tracked to identify how fast the entire economic as well as social life will be stabilized. The monitor ofthe vaccination progress, a machine learning based Regressor model is approached in this study. This tracking process has been applied on the data starting from 14^th December, 2020 to 24^th April, 2021. A couple of ensemble based machine learning Regressor models such as Random Forest, Extra Trees, Gradient Boosting, AdaBoost and Extreme Gradient Boosting are implemented and their predictive performance are compared. The comparative study reveals that the AdaBoostRegressor outperforms with minimized mean absolute error (MAE) of 9.968 and root mean squared error (RMSE) of 11.133.

The human oral microbiome refers to an ecological community of symbiotic and pathogenic microorganisms found in the oral cavity. The oral cavity is a suitable environment that provides various kinds of biological niches such as teeth, tongue, and oral mucosa. The oral cavity is the gateway between the external environment and the human body, maintaining oral homeostasis, protecting the mouth, and preventing disease. On the flip side, the oral microbiome plays an important role in triggering, development, and progression of oral and systemic diseases. Currently, disease diagnosis through the analysis of the human oral microbiome has been realized with the recent development of innovative detection technology, and is overwhelmingly promising compared to the previous era. It has been found that patients with oral diseases and systemic diseases have variations in the oral microbiome compared to normal subjects. This narrative review provides insight into the pathophysiological role that oral microbiome plays in influencing oral and systemic diseases, and updates the knowledge related to the oral microbiome over the past 30 years. A wide range of updates was provided with the latest knowledge of the oral microbiome to help researchers and clinicians in both academic and clinical aspects. The microbial community information can be utilized in non-invasive diagnosis and help develop a new paradigm in precision medicine, which will benefit human health in the era of post-metagenomics.

According to the literature, patients with chronic pain and mental disorders constitute a huge, heterogeneous group. However, it is known that social and psychological processes closely affect the level and expression of chronic pain. In this paper, we present a review of the literature, define methods of identifying pain biomarkers and consider the possibility of using them to assess pain in mental disorders. Group researchers searched PubMed, Scope, and Cochrane databases for "pain biomarkers in mental disorders" between 2011 and 2021. for available databases for full-text, peer-reviewed studies and review publications using the following keywords: pain biomarkers, neuroimaging pain, pain metabolomics, pain and psychiatric disorders, pain electroencephalography (EEG), serum pain biomarkers, saliva biomarkers, and diagnosis pain. The search included full-text articles, clinical trials, randomized controlled trials, and systematic reviews. Was used part of the PRISMA method to review the literature systematically. A literature search identified 283 studies based on the initially set inclusion and exclusion criteria. In the subsequent selection stages, 11 studies were selected for analysis. There are three main areas of the possible use of biomarkers for the clinical assessment of pain in psychiatric patients, neuroimaging, changes in metabolite levels in body fluids, and changes in gene expression. As a result of the review, individual pain mediators were distinguished that may be markers of pain in psychiatric patients. Some mediators indicate the specificity of pain and are of diagnostic importance. However, despite significant advances in research, most of the described biomarkers found in clinical trials assessing the severity and frequency of pain have no practical significance in psychiatric disorders. It is possible to diagnose pain based on neuroimaging using various methods, genetic methods, body fluids: blood and urine. Of the many, body fluid biomarkers are the most advanced. Discussion: Biomarker research is a dynamically developing field. The review has proposed new ways to diagnose pain by identifying pain biomarkers. Work presented pain diagnostics in psychiatric disorders based on biomarkers from various neuroimaging methods, blood and urine analysis. The possibility of new, effective techniques gives hope for the correct diagnosis of pain, especially in patients with mental disorders, which would allow for appropriate and adequate therapeutic therapies. In clinical practice is limited to a few methods. Assessment of pain biomarkers in body fluids (serum, saliva, and urine) seems to be the most practical and promising method of clinical application. Conclusions: There are new techniques that give hope for the correct diagnosis of pain, especially in patients with mental disorders, which will allow for their proper and adequate therapy. According to the literature, patients with chronic pain and mental disorders constitute a huge, heterogeneous group. However, it is known that social and psychological processes closely affect the level and expression of chronic pain.

Background: Superspreading events are important drivers of the SARS-CoV-2 pandemic. By analyzing two outbreaks associated with choir rehearsals in March 2020, we demonstrate the risk of indoor, long-range (LR) transmission and singing, to help prevent similar outbreaks. Methods: We conducted two retrospective cohort studies and obtained demographic, clinical, laboratory and contact data, performed SARS-CoV-2 serology, whole genome sequencing (WGS), calculated LR transmission probabilities, measured particle emissions of selected choir members, and calculated particle air concentrations and inhalation doses.Results: We included 65 (84%) and 42 (100%) members of choirs 1 and 2, respectively. WGS confirmed strain identity in both choirs and the primary case of choir 1 (transmitting presymptomatically). Particle emission rate when singing was 7 times higher compared to talking. In choir 1, the median concentration of primary cases’ emitted particles was 8 times higher, exposure at least 30 minutes longer and room volume smaller than in choir 2, resulting in markedly different estimated probabilities for LR transmission (median: 89% vs. 18%, 95%CI: 80-95% vs. 6-36%). Observed AR in choir 1 (89%) was significantly higher than in choir 2 (24%). According to a risk model, first transmission in choir 1 occurred likely after 7 minutes of singing. The number of inhaled particles emitted by an infectious case, sufficient to infect 50% of exposed, was calculated to 1039-2883 particles (95%CI).Conclusions: Even in large rooms, singing of an infectious person may lead to secondary infections through LR exposure within minutes. Given the potential for presymptomatic infectiousness, greatest caution is required wherever aerosols can accumulate.

Background: Patients in the postoperative period following bariatric surgery are at risk of developing eating disorders. This study aims to analyse the relation between bariatric surgery and the development and recurrence of eating disorders. Material and methods: Literature review was done on 15th November 2020. Fourteen studies that met the eligibility criteria were included for qualitative synthesis, and 7 studies for meta-analysis. Results: The prevalence of eating disorders in the postoperative period was 7.83%, based on the 7 studies in the meta-analysis. Binge eating disorder alone was 3.81%, which was the most significant factor, and addressed in 6 of these studies. Conclusion: The investigated studies have significant methodological limitations in assessing the relation between bariatric surgery and eating disorders, since they mostly present data on prevalence. PROSPERO CRD42019135614.

Circulating atypical cells (CAC) are released from a primary tumour site into peripheral blood and are indicators of cancer metastasis. CAC occur at very low frequency in circulating blood, and their detection remains challenging. Moreover, white blood cells (WBC) are the major contaminant in enriched CAC samples. Here, we developed matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) as a novel CAC characterization platform. Main spectra profiles (MSP) of normal and cancer cells were generated by MALDI-TOF MS, and a cell-main spectra database was then compiled and analysed using the MALDI Biotyper software. Logarithmic scores accurately predicted distinct cell types. The feasibility of this workflow was then validated using simulated samples, which were prepared by 5,000 WBC of three healthy individuals spiked with varying numbers (3, 6, 12, 25, 50 and 100) of lung, colon, or prostate cancer cells. MALDI-TOF MS was able to detect cancer cells down to six cells over the background noise of 5,000 WBC with significantly higher predictive scores as compared to WBC alone. Further development of cell-MSP database to cover all cancer types sourced from cell lines and patient tumours may enable the use of MALDI-TOF MS as a cancer-screening platform in clinical settings in the future.

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the Library of Integrated Network-based Cellular Signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-5-FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the 1) induction of cell cycle arrest in the S phase and 2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both c-mesenchymal–epithelial transition (MET)/ Kirsten Rat Sarcoma virus (KRAS)/ extracellular signal-regulated kinase (ERK) and c-MET/ phosphatidyl-inositol 3-kinases (PI3K)/ protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/ matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required to validate the results of the present study.

This review focuses on the evidence for neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD). EEG-Neurofeedback has been tested for about 45 years with latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

Acute high altitude illnesses are of great concern for physicians and people traveling to high altitude. High Altitude Pulmonary Edema (HAPE) can be better understood through the Oxygen Transport Triad which involves the Pneumo-Dynamic Pump (Ventilation), the Hemo-Dynamic Pump (Heart and circulation), and Hemoglobin. The two pumps are the first physiologic response upon initial exposure to hypobaric hypoxia. Hemoglobin is the balancing energy-saving time-evolving equilibrating factor. The increased hemoglobin at high altitude reduces the percentage of dissolved oxygen in the arterial oxygen content with respect to sea level. At high altitude, the acid-base balance must be adequately interpreted using the high altitude Van-Slyke correction factors. Pulse-oximetry measurements during breath-holding at high altitude allow for the evaluation of high altitude diseases. The Tolerance to Hypoxia Formula shows that, paradoxically, the higher the altitude the more tolerance to hypoxia. All organisms adapt physiologically and optimally to a high-altitude environment to survive. Reduction of pulmonary hypertension in HAPE through oxygen administration results in a favorable outcome.

Purpose: Kidney Transplant Recipients (KTRs) tend to develop infections with characteristic epidemiology, presentation and outcome. While infective endocarditis (IE) is among such complications in KTRs, literature is scarce. We describe the presentation, epidemiology, and factors associated with IE in KTRs. Methods: We performed a retrospective case/control study which included patients from two centers. First episodes of definite or possible IE (Duke criteria), in adult KTRs from January 2007 to December 2018 were included, as well as two controls per case, and followed until December 31 2019. Clinical, biological, and microbiological data and the outcome were collected. Survival was studied using the Kaplan-Meier method. Finally, we searched for factors associated with the onset of IE in KTRs by the comparison of cases and controls. Results: Seventeen cases and 34 controls were included. IE was diagnosed after a mean delay of 78 months after KT, mostly on native valves of the left heart only. Pathogens of digestive origin were most frequently involved (six Enterococcus spp, three Streptococcus gallolyticus and one Escherichia coli), followed by Staphylococci (three cases of S. aureus and S. epidermidis each). Among the risk factors evaluated only age was significantly associated with the occurrence of IE in our study (63.8 years for cases vs. 55.6 years for controls, P=0.03) Patient and death-censored graft survival were greatly diminished five years after IE compared to controls being 50.3% vs. 80.6% (p<0.003) and 29.7% vs. 87.5% (p<0.002), respectively. Conclusion: IE in KTRs is a disease that carries significant risks both for the survival of the patient and the transplant.

Alzheimer’s Disease (AD) is a significant health concern worldwide with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary etiological features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and drugs in clinical practice present numerous side effects. Lack of effective diagnostic techniques prevents the early prognosis of disease, resulting in a gradual deterioration in the quality of life. Furthermore, the mechanism of cognitive impairment and AD pathophysiology is poorly understood. Microfluidics exploits different microscale properties of fluids to mimic environments on microfluidic chip-like devices. These miniature multichambered devices can be used to grow cells and 3D tissues in vitro, analyze cell-to-cell communication, decipher the roles of neural cells like microglia, and gain insights into AD pathophysiology. This review focuses on the applications and impact of microfluidics on AD research. We discuss the technical challenges and possible solutions provided by this new cutting-edge technique to understand disease-associated pathways and mechanisms.

Purpose: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population. Materials and Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 <65-year-old (yo), group 2 >65 yo, analyzed for tolerance and efficacy. Results: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3–4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5–27.9) and 16.3 M (CI: 14.5–26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4–9.9) and 7.7 M (CI: 5.8–11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6). Conclusion: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable.

Ongoing concerns regarding the morbidity and mortality from cancer-associated thrombosis led the European Cancer Patient Coalition (ECPC), the voice of cancer patients across Europe, to create a pan-European cancer-associated awareness patient survey to assess CAT knowledge among a large population of patients with cancer. The ECPC survey represents the largest of its kind amongst patients/caregivers with CAT and identified significant gaps in patient awareness and knowledge of CAT. It also identified a need for educational CAT-related discussions and interventions between healthcare professionals and patients with cancer and their caregivers. The aim of this paper is to highlight these gaps and to provide healthcare professionals with awareness of what information should be shared with patients/caregivers as well as how and when that information should be provided. Notably, the importance of providing information on CAT risk and risk factors, how to reduce their risk of CAT, the role of anticoagulant prophylaxis and treatment (short- and long-term) including possible side-effects, and finally how to early identify CAT symptoms. Here we outline what type of information should be provided, as well as when and how to best discuss CAT with our oncology patients and their caregivers along the cancer care continuum, to reduce the risk of CAT and associated complications with a goal of improving patient outcomes.

Levodopa remains the primary drug for controlling motor symptoms in Parkinson's disease through the whole course, but over time complications develop in the form of dyskinesias, which gradually become more frequent and severe. These abnormal, involuntary, hyperkinetic movements are mostly characteristic of the ON phase and reflect an excess of exogenous levodopa. They may also occur during OFF phase, or in both phases. Over the past 10 years, the issue of levodopa-induced dyskinesia has been the subject of research into both the substrate of this pathology and potential remedial strategies. The purpose of the present study was to review the results of recent research on the background and treatment of dyskinesia. To this end, databases were reviewed using a search strategy that included both relevant keywords related to the topic and appropriate filters to limit results to English-language literature published since 2010. Based on the selected papers, the current state of knowledge on morphological, functional, genetic, and clinical features of levodopa-induced dyskinesia, as well as pharmacological, genetic treatment and other therapies such as deep brain stimulation are described.

The Asian elephant (Elephas maximus) is one of the largest herbivore mammals in the world. A portion of the total elephant population is under human care, where health problems such as skin lesions and decreased appetite are reported. The objective of this study was to apply the therapeutic properties of cannabidiol (CBD) to aid treatment of palmar abscesses and a suboptimal food intake in a female Asian elephant in Mexico. A CBD-isolate compounded medication was administered orally at a dose of 0.05 mg/kg/day. CBD administration showed positive effects such as reduction in abscess size, decreased food selectivity, increased food intake, weight gain and increased mobility. More research in elephants is needed to understand their cannabinoid pharmacodynamics and pharmacokinetics and proposing a dosage range and therapeutic applications for this species.

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol related disorder in persons with bipolar disorder (BD). The study population included 1,268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol related disorder including alcohol use disorder (AUD). Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol related disorder diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge automated neuropsychological test battery (CANTAB) on tablet computer: the 5-choice serial reaction time task, or, reaction time (RT) test and the Paired Associative Learning (PAL) test. Association between RT-test and alcohol use was analyzed with log-linear regression, and eβ with 95% confidence intervals (CI) are reported. PAL first trial memory score was analyzed with linear regression, and β with 95% CI are reported. PAL total errors adjusted was analyzed with logistic regression and odds ratios (OR) with 95% CI are reported. After adjustment for age, education and housing status, hazardous drinking was associated with lower median and less variable RT in females while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores in females. Our findings of positive associations between alcohol use and cognition in persons with bipolar disorder are unique.

Glucocorticoids (GCs) have been the mainstay of immunosuppressive therapy in solid organ transplantation (SOT) for decades due to their potent effects on the innate immunity and tissue protective effects. But, some SOT centers are reluctant to administer GCs for long-time due to the various side effects. This review summarizes advantages and disadvantages of GCs in SOT. PubMed and Scopus databases were searched from 2011 to April 2021 using search syntaxes cover “transplantation” and “glucocorticoids”.GCs are used in transplant recipients, transplant donors, and organ perfusate solution to improve transplant outcomes. In SOT recipients GCs are administered as induction and maintenance immunosuppressive therapy. GCs are also the cornerstone to treat acute anti-body- and T-cell-mediated rejections. Addition of GCs to organ perfusate solution and pretreatment of transplant donors with GCs are recommended by some guidelines and protocols to reduce ischemia-reperfusion injury peri-transplant. GCs with low bioavailability and high potency for GC receptors such as budesonide, nanoparticle-mediated targeted delivery of GCs to specific organs, and combination use of dexamethasone with inducers of immune-regulatory cells are new methods of GC usage in SOT patients to reduce side effects or induce immune-tolerance instead of immunosuppression. Various side effects on different non-targeted organs/tissues such as bone, cardiovascular, neuromuscular, skin, and gastrointestinal tract have been noted for GCs. There are also potential drug-drug interactions for GCs in SOT patients.

The global burden of stroke is still high, particularly in developing countries, with hypertension serves as the main risk factor. Knowledge related to stroke is essential to establish better prevention strategies. This study aimed to identify factors associated with stroke awareness among hypertensive patients in Indonesia. This was a cross-sectional study conducted in five Community Health Centers in Indonesia. We used a standardized questionnaire to asses stroke awareness and the influencing factors. The knowledge on hypertension was assessed using Hypertension Knowledge Level Scale (HK-LS). Multivariate logistic regression analysis was performed to measure factors associated with stroke awareness. A total of 457 hypertensive patients were included. Majority of patients (77.46%) had low stroke awareness. Having higher knowledge on hypertension, higher income, and a history of previous stroke were associated with higher level of stroke awareness (odds ratio [OR] 1.878, 95%CI 1.176-2.999, p 0.008; OR 1.887, 95%CI 1.170-3.045, p 0.009; OR 5.276, 95%CI 2.210-12.594, p<0.001, respectively). This study suggests that knowledge on hypertension, income, and history of previous stroke are factors which may influence the level of stroke awareness. This emphasizes the need to provide better campaign and education program to raise stroke awareness in a community setting.

This study aimed to characterize the genetic subtypes of HCV-GT4 and identify the presence of natural occurring resistance-associated substitutions (RASs) in Saudi Arabia patients. A total of 17 GT4 patients was analyzed. Sequence analysis of NS3, NS5A and NS5B regions was performed by direct sequencing. In addition, phylogenetic analysis was used to determine genetic subtypes, RAS and polymorphisms. Nine patients were infected by a GT4a, one with GT4o, 3 with GT4d. The remaining four patients were infected with a recombinant virus (GT4a+GT4o in three patients, GT4c+GT4d in a patient). Natural RASs were found in six patients (35%), including three infected by GT4a, two by GT4a+GT4o and one patient infected by GT4c+GT4d. In particular, NS3-RAS V170I was demonstrated in three patients, while NS5A-RASs (L28M, L30R, L28M+M31L) were detected in the remaining three patients. All patients were treated with sofosbuvir plus daclatasvir; three patients were lost to follow-up whereas 14 patients completed the treatment. A sustained virological response (SVR) was obtained in all but one patient carrying NS3-RAS V170I who later relapsed. GT4a is the most common subtype in this small cohort of Saudi Arabia patients infected with hepatitis C infection. Natural RASs were observed in about a third of patients, but only one of them showed a treatment failure.

Galangin(Gal) is a natural active flavonoid compound separated from the roots and rhizomes of Alpinia ofcinarum Hance. Modern pharmacological studies have shown that Gal has a variety of biological activities such as anti-tumor, anti-fungal, anti-bacterial, anti-inflammatory, anti-ischemic stroke, suppressing vitiligo and Alzheimer’s disease, etc. The purpose of this research was to prepare a galangin self-microemulsion drug delivery system (Gal-SMEDDS) and compare its anti-oxidant activity and pharmacokinetics with free Gal.The average particle size of the prepared Gal-SMEDDS was approximately 21.33 nm, the polydispersity index was 0.096, the zeta potential was -4.09 mV, and the entrapment efficiency was 96.74%. Compared with free Gal, the release of Gal-SMEDDS was improved in vitro release experiment. Cell experiments showed that Gal had obvious anti-oxidation effect, and the effect of Gal-SMEDDS was better than that of free Gal. In vivo pharmacokinetic experiments showed that the pharmacokinetic parameters of Gal-SMEDDS were better than that of free Gal, which indicated that the self-microemulsion drug delivery system(SMEDDS) effectively increases the oral bioavailability of Gal and alters its pharmacokinetic parameters, such that it may be effective in the treatment of anti-oxidant.

Objectives To examine the comorbidity burden in patients with rheumatoid arthritis (RA) patients using a nationwide population-based cohort by assessing the Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Index (ECI), Multimorbidity Index (MMI), and Rheumatic Disease Comorbidity Index (RDCI) scores and to investigate their predictive ability for all-cause mortality. Methods We identified 24,767 RA patients diagnosed between 1998–2008 in Taiwan and followed up until December 31, 2013. The incidence of comorbidities was estimated in three periods (before, during, and after the diagnostic period). The incidence rate ratios were calculated by comparing during vs. before and after vs. before the diagnostic period. One- and 5-year mortality rates were calculated and discriminated by low and high-score groups and modified models for each index. Results The mean score at diagnosis is 0.8 in CCI, 2.8 in ECI, 0.7 in MMI, and 1.3 in RDCI, and annual percentage changes are 11.0%, 11.3%, 9.7%, and 6.8%, respectively. The incidence of any increase in the comorbidity index is significantly higher in the periods of ‘during’ and ‘after’ the RA diagnosis (incidence rate ratios for different indexes: 1.33-2.77). The mortality rate significantly differs between the high and low-score groups measured by each index (adjusted hazard ratios: 2.5-4.3 for different indexes). CCI is slightly better in the prediction of 1- and 5-year mortality rates. Conclusion Comorbidities are common before and after RA diagnosis, and the rate of accumulation accelerates after RA diagnosis. All four comorbidity indexes are useful to measure the temporal changes and to predict mortality.

Abstract: Turmeric is a plant with multiple medicinal attributes. One of them being its analgesic effect. In this project the analgesic effect of the plant was evaluated with an inflammatory pain model: the 5% formalin model. Turmeric was administered to 250 g male Wistar rats (6 ± 2) provided by the Health Science department’s vivarium. The dose-response curve of the plant was per-formed observing the analgesic effect. Once the dose was selected, they were administrated within different turmeric protocols. 400 mg orally every 24 h for two weeks, another group with turmeric ad libitum for two weeks, the control group with 0.9% saline solution for two weeks, and a group with administration of metamizole prior to evaluation with 5% formalin. Subsequently, each rat was evaluated by 5% formalin intraplantarly and the number of rat paw twitches per 1 h was observed. The analysis of the data generated through the obtained results was carried out. The dose of 400 mg of oral turmeric was administered for two weeks without observing any collateral effects. An excellent analgesic effect was found in this protocol, as well as, in the ad libitum administration for two weeks compared to the control group. Likewise, turmeric presents a milder effect than metamizole, a well-known analgesic.

This post-hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visit and hospitalization in women and men. During the study period (January 2007 – December 2018), 61,855 reports of ADE leading to ED visit were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidi-ties were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing and adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.

Abstract Diabetes mellitus (DM) is an independent risk-factor for cardiovascular diseases. Plant-based dietary-patterns have been shown to positively impact the effects this cardiovascular risk-factor. The purpose of this study is to investigate the association of adherence to moringa, plantains, moringa-plantain combined, and other plant based dietary-patterns with glycemic-control among persons with type-2-diabetes Mellitus (T2DM). Facility-based cross-sectional-study was conducted among 530 T2DM patients in Ghana. Structured-questionnaires were used to collect demographic, anthropometric, and clinical variables. Adherence to plant-based dietary-patterns were assessed with 24-hour dietary-recall questionnaire. SPSS version-22 was used in data analysis. BMI, HbA1c%, HDL-cholesterol and LDL-cholesterol were significantly correlated with adherence to plant-based dietary-patterns (p-value < 0.05). After adjusting for confounders, adherence to: Plantain diets, standardized regression coefficient β (95%CI): -0.098 (-0.321, -0.022), Yam, β (95%CI): 0.148 (0.066, 0.496), Moringa diets β (95%CI): -0.095 (-0.325,-0.011) and Bean-diets β (95%CI): -0.112 (-0.577-.007) were significantly associated with glycemic control. Also adherence to: Plantain-moriga combined diets β (95%CI): -0.406 (-0.413, -0.049) and Plantain-beans combined diets β (95%CI): -0.128 (-0.188, -0.038) were significantly associated with glycemic control. Adherence to Plantain, Yam, Beans, Plantain-moriga combined diets, and Plantain-beans combined diets could be associated with glycemic control. Keywords: Diabetes mellitus, Adherence, Moringa, Plantain, Glycemic control, Ghana.

UV-Visible spectroscopy method has been developed for the analysis of Thiamine in biological and pharmaceutical product, based on a chromogenic derivatizing reaction using PDAB (P- dimethyl amino benzaldehyde) reagent. A Central Composite Design (CCD) design with response surface methodology was executed for optimization of experimental conditions of drug with a smaller number of experimental trials. Three independent factors, the concentration of PDAB, the volume of PDAB reagent, and volume of HCl, were used to construct a mathematical model and study the effects of these independent factors on responses as absorbance. The colored complex exhibits a Red shift with absorption maximum λmax at 425 nm, which was selected as the analytical wavelength. The drug seems to be linear, which was established via the regression analysis from 5-30 μgmL-1, with an R2 value of 0.998.The % RSD for intraday and interday precision was < 2%, with good recovery ranging from 95.02 to 101.43% with biological and pharmaceutical samples. LOD and LOQ of the developed method were found to be 1.51 μg mL-1 and 4.57 μg mL-1.This method can be used in routine analysis of pharmaceutical products containing aromatic primary amines along with an estimation of biological samples like urine, blood, sweat, faeces.

Phytonutrients are plant foods that contain many natural bioactive compounds, called phytochemicals, which expose specific biological activities. These phytonutrients and their phytochemicals may play an important role in health care maintaining normal organism functions (as preventives) and fighting against diseases (as therapeutics). Phytonutrient’s components are the primary metabolites (i.e., proteins, carbohydrates, and lipids) and phytochemicals or secondary metabolites (i.e., phenolics, alkaloids, organosulfides, and terpenes). For years, several phytonutrients and their phytochemicals have demonstrated specific pharmacological and therapeutic effects in human health such as anticancer, antioxidant, antiviral, anti-inflammatory, antibacterial, antifungal, and immune response. This review summarizes the effects of the most studied or the most popular phytonutrients (i.e., turmeric, garlic, cinnamon, graviola, and oregano), and any contraindication found. This article also calculated the physicochemical properties of the main phytochemicals in the selected phytonutrients using Lipinski’s, Veber’s and Ghose’s rules. Based on our revisions for this article, all these phytonutrients have consistently shown several in vitro, in vivo, and clinical studies with great potential as preventives and therapeutics on many diseases.

Retinoblastoma is the most common intraocular paediatric eye cancer. It accounts for approximately 11% of primary cancers occurring in the first age of life, with 95% of diagnoses before 5 years of age [1-3]. Since retinoblastoma is very aggressive, early diagnosis and prompt treatment are vital for children to preserve their sight and life. In western countries in Europe and North America, retinoblastoma is diagnosed early so the chances of saving the patient’s life and preserving vision are good. However, in large regions of Africa and Asia, where the diagnosis of retinoblastoma is delayed, the deadly effect is observed [2-5]. In these regions, socioeconomic factors and poor recognition of the seriousness of the disease result in a high mortality rate of up to 70%. At the same time, the mortality rate in Europe and North America is 3-5 % [2]. Besides, the incidence of retinoblastoma also varies by race and region, from 40 to 60 per million live births, which corresponds to 1 per 16,000 - 24,000 live births, with the greatest disease burden recorded in the countries of Asia and Africa where the highest birth rates are recorded [2,3 However, the nationwide studies of the retinoblastoma epidemiology have been conducted in many countries, such as Sweden, Finland, Netherlands, Singapore, Great Britain, United States of America, Korea and Taiwan, there is a lack of data from Eastern European countries like Poland [1,3-11]. The management of retinoblastoma may also differ between developed and developing countries. The current strategy of retinoblastoma treatment aims to save the life, eye, vision and cosmetics of the child, in order of priority. Medical management of retinoblastoma includes surgical treatment (enucleation), external beam radiotherapy, systemic chemotherapy with or without focal therapies such as cryotherapy, laser photocoagulation and plaque radiotherapy. Recently, intra-arterial and intravitreal chemotherapies have been used to treat retinoblastoma with the ability to save globes that otherwise would have been enucleated [2,3]. The present study aimed to investigate the incidence and characteristics of retinoblastoma in the overall population of Poland in the years 2010-2017 and to report the changes that occurred during that period.

Background: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like physiosomatic (previously known as psychosomatic) symptoms.Aims: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest CT-scan anomalies (CCTAs), oxygen saturation (SpO₂), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs).Method: The above biomarkers were assessed in 60 COVID-19 patients and 30 heathy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales. Results: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. Moreover, one common “infection-immune-inflammatory (III) core” underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms.Discussion: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which both may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.

Background. Until now, cost of allergy treatment in insured public health care system and non-insured self-financing private health care system in Indonesia has not been well documented and published, as well as the cost of allergy treatment with subcutaneous immunotherapy. Objective. To evaluate the clinical and cost benefits of allergic rhinitis treatment in children with subcutaneous immunotherapy in non-insured self-financing private health care system. Methods. A retrospective cohort study conducted from 2015 until 2020, compared clinical improvement and health care costs over 18 months in newly diagnosed AR children who received SCIT versus matched AR control subjects who did not receive SCIT, with each group consisting of 1,098 subjects Results. Decrease of sp-HDM-IgE level (kU/ml) from 20.5 + 8.75 kU/ml to 12.1 + 3.07 kU/ml had been observed in the SCIT group. To reduce the symptom score of allergic rhinitis by 1.0 with SCIT it costs IDR 21,753,062.7 per child, for non SCIT it costs IDR 104,147,878.0 per child. Meanwhile, to reduce the medication score (MS) by 1.0 with SCIT it costs Rp. 17,024,138.8 while with non SCIT it costs Rp. 104,147,878.0. Meanwhile, to lower combination symptoms and medication score (CSMS) by 1.0, with SCIT it costs IDR 9,550,126.6, while with non SCIT it costs IDR 52,073,938.9. Conclusion. In conclusion, this first Indonesia-based study demonstrates substantial health care cost savings associated with SCIT for children with AR in an uninsured private health care system and provides strong evidence for the clinical benefits and cost-savings benefits of AR treatment in children.

The emergence of carbapenemase-producing Enterobacteriaceae has limited therapeutic options and presents a major public health problem. Resistances against carbapenems in this bacterial family are mostly conveyed by metallo-beta-lactamases (MBL) including VIM, which are often encoded on resistance plasmids. We characterized four VIM-positive isolates that were obtained as part of a routine diagnostic screening from two laboratories in north-eastern Germany be-tween June and August 2020. Whole-genome sequences were generated to address a) their phylo-genetic properties, b) their plasmid content, and c) the underlying mechanisms of resistance and virulence. In addition, we performed phenotypic antibiotic and mercury resistance analyses. The genomic analysis revealed three different bacterial species including C. freundii, E. coli and K. oxytoca with four different sequence types. All isolates were geno- and phenotypically multi-drug-resistant (MDR). Three isolates of four carried identical VIM-1-resistance plasmids, which – in addition – encoded for a mercury resistance operon and showed some similarity to two ex-ternal plasmid sequences. The distribution of virulence features among the genomes was limited. Our results highlight the circulation of an identical VIM-1-resistance plasmid in three of four bacterial isolates of different Enterobacteriaceae in north-eastern Germany.