Objectives To develop and validate a prediction model for 28-day in-hospital mortality among adult patients critically ill with COVID-19 in the UK. Design Observational cohort study. Setting 287 adult critical care units in England, Wales and Northern Ireland, of which 260 admitted at least one eligible patient. Participants 10,933 patients with confirmed COVID-19 of whom 10,401 were eligible (excluding 532 patients with a duration of critical care less than 24 hours and 1 patient with unknown 28-day outcome): 8,666 development (March-April 2020) and 1,735 temporal validation (May-August 2020). Main outcome measures 28-day in-hospital mortality from start of critical care. Results Two models were developed using 14 patient level predictors selected from 30 candidate predictors, with and without adjustment for calendar time. In the temporal validation data, the model discrimination was maintained (c index 0.78) but calibration was poor, particularly for the model not adjusted for calendar time (ratio of observed to predicted mortality 0.74 versus 0.88 for the model adjusted for calendar time). Conclusions We developed and validated a prediction model for 28-day in-hospital mortality for patients critically ill with COVID-19. Although absolute predictions were inaccurate due to changing outcomes, the models will support risk-adjustment in analyses and monitoring changes in risk-adjusted outcome over time.

The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5’UTRs onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5´UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad-spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

This bibliometric review is aimed to analyze the top 100 most-cited publications in dentistry and to compare its outcomes with similar analysis done by Feijoo et al., [1]. A literature search was performed using the Elsevier's Scopus without any restriction of language, publication year or study design. Of 336381 articles, the top 100 were included based on their citation count which ranged from 638 to 4728 citations (Feijoo et al., 326 to 2050). Most productive decade was the 2000s with 40 articles on the list (Feijoo et al., 1980s: 26). Marx RE (7%) was the major contributor in this study (Feijoo et al., Socransky SS: 9%) and a whopping 48% articles generated from the USA. 26% of top 100 articles focused periodontology (Feijoo et al., periodontology: 43%), while 17% of the total were published in the Journal of Dental Research (Feijoo et al., Journal of Clinical Periodontology: 20%). Most of the publications were narrative reviews/expert opinion (36%), (Feijoo et al., case series: 22%) and were within the evidence level V (64%) (Feijoo et al., 54%). The citation count that a paper secures is not necessarily a reflection of research's quality, however, the current analysis provides latest citation trends in dentistry.

Older adults with diabetes are at elevated risk of complications following hospitalization. Home health care services mitigate the risk of adverse events and facilitate a safe transition home. Building on prior findings of racial/ethnic disparities in post-acute referral and utilization of home health, this study examined timing of home health care initiation and 30-day rehospitalization outcomes. Using linked Medicare administrative, assessment, and claims datasets (2014-2016), we identified 209,150 Medicare beneficiaries, age 50 and older, who were referred to post-acute home health following a diabetes-related index hospitalization. Multivariate logistic regression models included patient demographics, neighborhood area deprivation, and rural/urban setting. Home health care initiated within one week was associated with lower risk of 30-day rehospitalization (days 0-2, OR=0.88, 95% CI 0.86-0.91; days 3-7, OR=0.87, CI 0.84-0.90). In contrast, a late start of services (days 8-14) was associated with a higher risk of 30-day rehospitalization (OR=2.2, CI 2.0-2.3). This pattern of results was observed across all racial/ethnic patient groups. However, racial/ethnic minority patients were less likely to receive timely home health care services compared to white patients. Timely initiation and coordination of home health care is one strategy to improve outcomes following diabetes-related hospitalizations that benefits older adults of all racial/ethnic groups.

Mastocytosis is characterized by pathological accumulation of mast cells (MC) in various organs. In these patients, MC may degranulate and thereby contribute to clinical symptoms, especially when a concomitant allergy is present. However, MC activation can not only be induced by high-affinity receptors for IgE, but also by anaphylatoxins, neuropeptides, IgG immune complexes, complement-components, drugs, products of bacteria or parasites, as well as physical factors such as heat, cold, vibration, stress, sun, or physical effort. Symptoms due to mediators released by activated MC may develop in adults suffering from systemic mastocytosis, but also evolve in children who usually have cutaneous mastocytosis (CM). Clinically, CM is otherwise characterized by typical brown, maculopapular skin lesions or mastocytoma associated with a positive Darier’s sign. Pruritus and flushing are common and blistering may also be recorded, especially in diffuse CM (DCM). Pediatric patients with mastocytosis may also have gastrointestinal, respiratory, and neurologic complaints. Although anaphylaxis is not a typical finding, pediatric patients with massive skin involvement and high tryptase levels have a relatively high risk to develop anaphylaxis. This paper reviews MC mediator-related symptoms and anaphylaxis in children with mastocytosis, with special emphasis on risk factors, triggers, and management.

Alzheimer’s disease and related dementias (ADRD) remain a public health challenge in developing counties. We developed a needs-based essential care service package (ECSP) for care planning of persons living with dementia (PLWD) using a cross-sectional survey among PLWD in institutions in six cities in China (n= 1,299). Face-to-face interviews were conducted with caregivers of PLWD by trained staff between 2018 and 2019. Care service needs and utilization by the level of cognitive impairment were summarized. The average age of PLWD was 80.7 years. 76% of participants had severe cognitive impairment. The needs-based ECSP with 30 service items would be sufficient in supporting care services of PLWD in China, of which seven items are core care. The selection plan for ECSP at different levels is designed as “General Care Services + Selective Care Services”, in which service items for low-, mid-and high-level care for PLWD are 7+3, 7+6, and 7+10, respectively. The findings provide the first large-scale data on service needs and utilization of PLWD in mainland China. The ECSP for PLWD advanced in the paper was a practicable and effective quantitative management means. It is deserved to application in a large scale.

Purpose: To report the early clinical outcomes of combining intensity‐modulated radiation therapy (IMRT) and intensity‐modulated proton therapy (IMPT) in comparison with IMRT alone in treating the oropharynx cancer (OPC) patients. Materials and Methods: The medical records of 148 OPC patients were retrospectively reviewed, who underwent definitive radiotherapy (RT) with concurrent systemic therapy, from January 2016 till December 2019 at Samsung Medical Center. During the 5.5 weeks’ RT course, the initial 16 (or 18) fractions were delivered by IMRT in all patients, and the subsequent 12 (or 10) fractions were either by IMRT in 81 patients (IMRT only) or by IMPT in 67 (IMRT/IMPT combination), respectively, based on comparison of adaptive re-plan profiles and availability of equipment. Propensity‐score matching (PSM) was done on 76 patients (38 from each group) for comparative analyses. Results: With the median follow‐up of 24.7 months, there was no significant difference in overall survival and progression free survival between groups, both before and after PSM. Before PSM, IMRT/IMPT combination group experienced grade ≥3 acute toxicities less frequently: mucositis in 37.0% and 13.4% (p<0.001); and analgesic quantification algorithm (AQA) in 37.0% and 19.4% (p=0.019), respectively. The same trends were observed after PSM: mucositis in 39.5% and 15.8% (p=0.021); and AQA in 47.4% and 21.1% (p=0.016), respectively. In multivariate logistic regression, grade ≥3 mucositis was significantly less frequent in IMRT/IMPT combination group, both before and after PSM (p=0.027 and 0.024, respectively). AQA score ≥3 was also less frequent in IMRT/IMPT combination group, both before and after PSM (p=0.085 and 0.018, respectively). Conclusions: In treating the OPC patients, with comparable early oncologic outcomes, more favorable acute toxicity profiles were achieved following IMRT/IMPT combination than IMRT alone.

Background: Risk tratification based on pre-test probability may improve the diagnostic accuracy of temporal artery high-resolution compression sonography (hrTCS) in the diagnostic workup of cranial giant cell arteriitis (cGCA). Methods: A logistic regression model with candidate items was derived from a cohort of patients with suspected cGCA (n = 87). The diagnostic accuracy of the model was tested in the derivation cohort and in an independent validation cohort (n = 114) by receiver operator characteristics (ROC)-analysis. The clinical items were composed to a clinical prediction rule, integrated into a stepwise diagnostic algorithm together with CRP-values and hrTCS-values. Results: The model consisted of 4 clinical variables (age &gt; 70, headache, jaw claudication, anterior ischemic optic neuropathy). The diagnostic accuracy of the model for discrimination of patients with and without a final clinical diagnosis of cGCA was excellent in both cohorts (AUC 0.96 and AUC 0.92, respectively). The diagnostic algorithm improved the positive predictive value of hrCTS substantially. Within the algorithm, 32.8% of patients (derivation cohort) and 49.1% (validation cohort) would not have been tested by hrtCS. None of these patients had a final diagnosis of cGCA. Conclusion: A diagnostic algorithm based on a clinical prediction rule improves the diagnostic accuracy of hrTCS.

The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

This study aimed to analyze the responsiveness of the 5STS test among stroke patients and to estimate the MCIDs for different severity levels of community ambulation and stages of recovery. The 5STS and comparator instruments [gait speed and Functional Ambulatory Category (FAC)] were evaluated at baseline. These measures were repeated at 4 (Stage 1) and 8 weeks (Stage 2), together with the Global Rating of Change (GROC). The MCIDs were calculated with two anchor-based methods using the GROC as the external criterion. Responsiveness to change for the 5STS was estimated analyzing the correlation with changes in the two comparator instruments and their capacity to discriminate improvement. For the 5STS test, while the MCIDs of the limited community ambulators were similar in the two stages (around 3 s), those of the household ambulators decreased from 1.9 s to 0.72 s. Spearman's rho coefficients showed an acceptable correlation between changes in 5STS and changes for both the FAC and gait speed changes in both stages of recovery. Our study revealed that the 5STS is responsive to functional changes in patients with stroke and that their degree of severity and stage of recovery influence the MCID values of the 5STS.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

CCNs are specific type of matricellular proteins, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members in mammals. The architecture of CCN proteins is multimodular and comprises four distinct motifs. CCN proteins achieve their specific physiological functions by binding to integrin receptors. The CCN family has been implicated in both cure and disease with impacts on biological interactions, such as cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, immune functions, chondrogenesis, and wound healing. Breast cancer is the most commonly diagnosed cancer worldwide and the leading cause of cancer mortality among women triggered by atypical expression of CCNs. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. Aberrant expression of CCN1 intensifies the proliferation of epithelial cells that line the lobes and ducts of the breast. Evidence also shows that the expression of CCN2 can ameliorate tumor growth and metastasis. However, CCN3 (NOV), CCN5 (WISP-2), and CCN6 (WISP-3) are consistent with neoplastic development and metastasis repression. Particular CCN members can develop tumors and cancer progression, whereas others can competitively counter the processes. Several studies have been conducted on CCN proteins and cancer in recent years. In our study, we intend to provide an overview of those research works while keeping breast carcinoma on focus. We believe that the importance of the CCN protein family in breast cancer should be reconsidered.

Muscle mass at admission is important to survive stroke, and stroke-induced sarcopenia is a serious problem because of its poor prognosis. Muscle mass measurement and monitoring are essential for appropriate re-habilitation and nutrition management. Several methods are used to assess skeletal muscle mass in stroke, such as computed tomography (CT), ultrasonography, bioelectrical impedance analysis, dual-energy X-ray absorptiometry, biomarkers, and anthropometrics. In stroke, a head CT is used to estimate muscle mass by measuring the temporal muscle. However, it is mostly retrospectively conducted due to radiation exposure. After stroke, limb muscle atrophy and diaphragm dysfunction are observed using ultrasound. However, ultrasound requires an understanding of the methods and skill. A bioelectrical impedance analysis can be used to assess muscle mass in patients after a stroke unless they have dynamic fluid changes. Dual-energy X-ray absorptiometry is used for follow-up after hospital discharge. Urinary titin N-fragment and serum C-terminal agrin fragment reflect muscle atrophy after stroke. Anthropometrics may be useful with limited resources. We summarized the features of each measurement and proved the recent evidence to properly measure and monitor skeletal muscle mass after stroke.

Background: Natural environment inhalation topography provides useful information for toxicant exposure, risk assessment and cardiopulmonary performance. Commercially available Wearable Respiratory Monitors (WRM), which are currently used to measure a variety of physiological parameters such as heart rate and breathing frequency, can be leveraged to obtain inhalation topography, yet little work has been done. This paper assesses the feasibility of adapting these WRMs for measuring inhalation topography. Methods: Commercially available WRMs were compiled and assessed for the ability to report chest motion, data analysis software features, ambulatory observation capabilities, participant acceptability, purchasing constraints and affordability. Results: The following WRMs were found: LifeShirt, Equivital EQ02 LifeMonitor, Smartex WWS, Hexoskin Smart Garment, Zephyr BioHarness, Nox T3&amp;A1, BioRadio, SleepSense Inductance Band, and ezRIP &amp; zRIP Durabelt. None of the WRMs satisfied all six assessment criteria in a manner enabling them to be used for inhalation topography without modification and development. Conclusion: The results indicate that there are WRMs with core technologies and characteristics that can be built upon for ambulatory inhalation topography measurement in the NE.

Adverse Outcome Pathways (AOP) provide structured frameworks for systematic organization of research data and knowledge. The AOP framework follows a set of key principles that allow for broad application across diverse disciplines related to human health, including toxicology, pharmacology, virology and medical research. The COVID-19 pandemic engages a great number of scientists world-wide and data is increasing with exponential speed. Diligent data management strategies are employed but approaches for systematically organizing the data-derived information and knowledge are lacking. We believe AOPs can play an important role in improving interpretation and efficient application of scientific understanding of COVID-19. Here, we outline a newly initiated effort to streamline collaboration between scientists across the world towards development of AOPs for COVID-19, and describe the overarching aims of the effort, as well as the expected outcomes and research support that they will provide.

Skin involvement is an overlooked aspect in the management of paediatric patients with type 1 diabetes. A comprehensive search of published literature using the PubMed database was carried out using the following key terms: “children”, “pediatric/paediatric patients”, “skin”, “skin disorders”, “type 1 diabetes”. Dermatological side effects are frequently observed among diabetic children and adolescents. Insulin-induced lipodystrophies and allergic contact dermatitis caused by insulin pumps or glycaemic sensors are the most common skin reactions in these patients. Furthermore, several diabetes-associated skin diseases such as necrobiosis lipoidica, granuloma annulare, vitiligo, and bullosis diabeticorum may already be present in paediatric age. Paediatric diabetes specialists should pay attention to their patients’ skin so as to recognize these disorders, identify the potential causes, and choose the most suitable treatment. Finally, the evaluation of skin concentrations of advanced glycation end-products using non-invasive diagnostic techniques may be used to assess the risk of chronic complications of diabetes as early as adolescence.

The use of whole-body vibration (WBV) for therapeutic purposes is far from being standardized and only very recently an empirical foundation for reporting guidelines for human WBV studies has been published. Controversies about safety and therapeutic dosage stll exist. The present study aimed to investigate the metabolic and mechanical effects of low-intensity WBV in according to the ISO 2631 norm on subjects with obesity. 41 obese subjects (BMI≥ 35 kg/mˆ2) were recruited to participate in a 3-week multidisciplinary inpatient rehabilitation program including fitness training and WBV training. During WBV the posture was monitored with an optoelectronic system with 6 infrared cameras (Vicon, Vicon Motion System, Oxford, UK). The primary endpoints were: variation in body composition, factors of the metabolic syndrome, functional activity (sit-to-stand and 6-min walking test), muscle strength, and quality of life. Secondary endpoints were: modification of irisin, testosterone, growth hormone, IGF1 levels. We observed significant changes in salivary irisin levels, Group 2 (p&lt;0.01) as compared to the control group, while muscle strength, function, and other metabolic and hormonal factors did not change after a 3-week low-intensity WBV training respect control group. Future studies are needed to deeper investigate the potential metabolic effect of low-intensity WBV in managing weight.

Hazardous toxic metals, such as lead and cadmium, and to a lesser extent aluminum, are extensively recognized as detrimental for health following ingestion within food and water, or following inhalation. Gut and food-derived microbes, by interacting with heavy metals, may actively or passively modulate their bioavailability inside the gut, either by adsorption or by sequestration. Such a bioremediation within the gut implies the selection of safe microbes, based on their specific capacities to immobilize metals. We investigated the metal removal ability of 225 bacteria toward the potential harmful trace elements lead, cadmium and aluminum in vitro, using Inductively Coupled Plasma Mass Spectrometry analysis. Interspecies and intraspecies comparisons were addressed and discussed among bacteria from the phylum Firmicutes, which are mostly lactic acid bacteria, including Lactobacillus spp, with some Lactococcus, Pediococcus and Carnobacterium representatives, Actinobacteria as well as Proteobacteria. The effect on mixture of lead and cadmium was also investigated. Although the purpose of such a screening is so far not to elucidate each of the various strain specific- and metal dependent- mechanisms of heavy metal removal, we identified potential bacteria which are able to alleviate Pb(II) and Cd(II) concerns in order to propose performing candidate probiotics for metal xenobiotic bioremediation.

The International Health Regulations (2005) promote national capacity in core institutions so countries can better detect, respond to and recover from public health emergencies. In accordance with the ‘all hazards’ approach to public health risk, this systematic review examines poisoning and toxic exposures in Myanmar. A systematic literature search was undertaken to find articles pertaining to poisoning in Myanmar published between 1998 and 2020. A number of poisoning risks are identified in this review including snakebites, heavy metals, drugs of abuse, agro-chemicals and traditional medicine. Patterns of poisoning presented in the literature diverge from poisoning priorities reported in other lower-middle income countries in the region. The expe-rience of professionals working in a Yangon-based poison treatment unit indicates that frequently observed poisoning as a result of substances including pharmaceuticals, methanol, and petroleum products were absent from the literature. Other notable gaps in the available research include assessments of the public health burden of poisoning through self-harm, household exposures to chemicals, paediatric risk and women’s occupational risk of poisoning. There is a limited amount of research available on poisoning outcomes and routes of exposure in Myanmar. Further inves-tigation and research is warranted to provide a more complete assessment of poisoning risk and incidence.

With the development of general anesthesia techniques and anesthetic substances, brought new horizons for the expansion and improvement of surgical techniques. Nevertheless, more complex surgical procedures brought a higher complexity and longer duration for general anesthesia that led to a series of adverse events such as hemodynamic instability, under- or overdosage of anesthetic drugs, as well as an increased number of post-anesthetic events. In order to adapt the anesthesia according to the particularities of each patient, the multimodal monitoring of these patients is highly recommended. Classically, general anesthesia monitoring consists of the analysis of vital functions and gas exchange. Multimodal monitoring refers to the concomitant monitoring of the degree of hypnosis and the nociceptive-antinociceptive balance. By titrating anesthetic drugs according to these parameters, clinical benefits can be obtained, such as hemodynamic stabilization, reduction of awakening times, and the reduction of post-operative complications. Another important aspect is the impact on the status of inflammation and the redox balance. By minimizing inflammatory and oxidative impact one can achieve a faster recovery that will lead to both increased patient satisfaction and an increase in patient safety. The purpose of this literature review is to present the most modern multimodal monitoring techniques, respectively to discuss the particularities of each technique.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, which predispose to more serious hepatic conditions. It ranges from simple liver steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and even end-stage liver disease. Since obesity became one of the most important health concerns wordwide, a considerable increase in the prevalance of NAFLD and other metabolic implications has been observed, both in adults, and children. Due to the coexistence of visceral obesity, insulin resistance, dyslipidemia, NAFLD is considered to be the hepatic manifestation of metabolic syndrome (MetS). These relationship between NAFLD and MetS led to set up in adults new term combining both of these conditions, called metabolic dysfunction-associated fatty liver disease (MAFLD). Based of these findings, we propose set of criteria, which may be useful to diagnose MAFLD in children and adolescents.

Background: It is unknown whether prolonged artificial hormonal environment during early fetal development affects the birthweight of singletons born after frozen-thawed embryo transfer (FET). Methods: A retrospective observational study included singleton births>22 weeks of gestation obtained after FET between 2013-2019 after endometrial preparation with ovulatory cycle (OC) or artificial cycle (AC). Our primary objective was to compare birthweight of singletons after FET between endometrial preparation by OC or AC. Secondary objectives included prolonged pregnancies, high birthweight, low birthweight, SGA and LGA rates. Multivariate analyses were performed considering potential confounding factors. Results: Among 198 singleton live births after FET, 112 were obtained with OC and 86 with AC. Prolonged pregnancies rate was higher in AC (25.6% vs. 7.1%, respectively, p=0.001). Mean birthweight was higher (+219g) in AC (3386g vs. 3167g, p=0.01; adjusted-p=0.052), as well as the rate of babies exceeding 4000g (16.3% vs. 2.7%, p=0.03, adjusted-p=0.015). The rate of babies <2500g was lower in AC (3.5% vs. 11.6%, respectively, p=0.050, adjusted-p=0.049). Conclusions: Since OC does not strain the chances of pregnancy and in the incomplete knowledge of the consequences of neonatal overweight on the future health of children, OC preparation could be advocated as first-line endometrial preparation in FET.

Aim To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods We conducted a retrospective monocentric observational study over a 3 years period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint or tyrosine kinase inhibitors (ICIs or TKIs) as of January-2017. Imaging reports were analysed by two physicians in consensus. Anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results Eighty patients were included and 195 couples of scans analysed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The more frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions Treatment monitoring with 18F-FDG

Superstition is a belief that is not based on scientific knowledge. Traditional healers usually use superstition in their practices to manage human health problems and diseases; such practices create a conflict with the medical profession and its evidence-based practices. Medical professionals confirm that this kind of practice is not safe to human health as it is done by untrained people (e.g., tradition healers) utilizing unsterilized instruments within unhygienic environments. Most of the cases eventually develop a variety of complications, which are sometimes fatal. Female genital mutilation, uvulectomy, oral mutilation (tooth bud extraction to cure “Ibyinyo”), and eyebrow incisions are examples of the many different types of superstitious practices which occur commonly in different parts of the world. We described how these traditional practices of superstition have been and continue to be performed in various parts of the world, their complications on oral and general health, and the ways such practices hinder modern medical practices. This paper aims to increase the awareness of these superstition-driven traditional and potentially harmful practices by promoting the importance of evidence-based medical practices.

In the present study, fish were exposed to sub-lethal doses of CuONPs (68.92 ± 3.49 nm) (10, 20, and 50 mg/L) for a long exposure period (25 days). Compared to the control group (0.0 mg/L CuONPs), a significant dose-dependent elevation in blood urea and creatinine values, serum alanine transaminase, aspartate transaminase, and alkaline phosphatase enzyme activities were evident in CuONPs-exposed groups (P &lt; 0.05). Fish exposure to 50 mg/L CuONPs significantly upregulated the transcription of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin 12, and interleukin 8), heat shock protein 70, apoptosis-related gene (caspase 3), and oxidative stress-related (superoxide dismutase, catalase, and glutathione peroxidase) genes in liver and gills of the exposed fish in comparison with those in the control group (P &lt; 0.05). Moreover, varying histopathological injuries were noticed in the hepatopancreatic tissues, posterior kidneys, and gills of fish groups correlated to the examined exposure dose of CuONPs. In summary, our results provide new insights and helpful information for better understanding the mechanisms of CuONPs toxicity in Nile tilapia at hematological, molecular levels, and tissue levels.

Polyphenols have been shown to possess outstanding anti-obesity properties. In this study, the effect of blue honeysuckle berry extract (BHBE) with high polyphenol content on lipid accumulation in adipocytes and the underlying mechanism were investigated for the first time. Composition analysis demonstrated that flavonoids (mainly flavonols and anthocyanins) were the primary polyphenols in BHBE, which contributed to its biological functions. The results of Oil Red O staining combined with triglyceride (TG) content determination showed that BHBE exhibited an obvious inhibitory effect on intracellular lipid accumulation in a dose-dependent manner. BHBE also reduced the protein level of fatty acid synthase (FAS) and increased the phosphorylation level of acetyl-CoA carboxylase (ACC), indicating that lipogenesis was suppressed by BHBE treatment. Moreover, BHBE was found to significantly promote the phosphorylation of AMP-activated protein kinase (AMPK) and further reduce the expression of key transcription factors (PPARγ, C/EBPα, and SREBP-1c) that regulate lipogenesis. In addition, the expression of beige adipocyte markers (Tmem26 and Cd137) and uncoupling protein 1 (UCP1) was increased in BHBE-treated adipocytes. In summary, we consider that BHBE inhibits lipid accumulation in adipocytes by suppressing lipogenesis as well as by promoting beiging of adipocytes. These results support blue honeysuckle berry as a candidate functional food against obesity.

Intravitreal injections (IVTs) of corticosteroids as triamcinolone acetonide (TA) are frequently used for the treatment of many vitreous and retinal disorders. However, IVTs are related to severe ocular complications. Lately, a topical ophthalmic TA loaded liposomes formulation (TALF) was designed to transport TA into the posterior segment of the eye when instilled in the ocular surface. To evaluate the safety, tolerability, and biologic activity of TALF, an animal study and a phase I clinical assay was performed. Moreover, four patients with diabetic macular edema (DME) were treated with TALF in order to explore the biologic activity of the formulation. No inflammation, lens opacity, swelling or intraocular pressure rising were recorded after the instillation of TALF in any of the animal or clinical study. Mainly, mild and transient adverse events such as dry eye (30%) and burning (30%) were reported. TALF improves significantly visual acuity and diminishes central foveal thickness in patients with DME. The current data demonstrate the safety, tolerability, and biologic activity of TALF. It seems that TALF can be used topically to treat vitreous and retinal diseases that respond to TA such as DME, avoiding the use of corticosteroids IVTs and its associated hazards.

Starting from early 2020, the COVID-19 pandemic has caused a morbidity and mortality excess worldwide. Containment strategies rely firstly on rapid and sensitive laboratory diagnosis with molecular detection of the viral genome in respiratory samples being the gold standard. Reliability of diagnostic protocols could be affected by SARS-CoV-2 genetic variability. In fact, mutations occurring during SARS-CoV-2 genomic evolution can involve the regions targeted by the diagnostic probes. Following a review of the literature and an in silico analysis of the most recently described virus variants (including the UK B 1.1.7 and the South Africa 501Y.V2 variants), we conclude that the described genetic variability should have minimal or no effect on the sensitivity of existing diagnostic protocols for SARS-CoV-2 genome detection. However, given the continuous emergence of new variants, the situation should be monitored in the future, and protocols including multiple targets should be preferred.

Optimal breastfeeding practices among mothers have been proven to have health and economic benefits, but evidence on breastfeeding practices among adolescent mothers in Bangladesh is limited. Hence, this study aims to estimate breastfeeding indicators and factors associated with selected feeding practices. The sample included 2554 children aged 0-23 months of adolescent mothers aged 12-19 years from four Bangladesh Demographic and Health Surveys collected between 2004 and 2014. Breastfeeding indicators were estimated using World Health Organization indicators. Selected feeding indicators were examined against potential confounding factors using univariate and multivariate analyses. Only 42.2% of adolescent mothers initiated breastfeeding within the first hour of birth, 53% exclusively breastfed their infants, predominant breastfeeding was 17.3%, and 15.7% bottle-fed their children. Parity (2-3 children), older infants and adolescent mothers who made postnatal check-up after two days were associated with increased exclusive breastfeeding (EBF) rates. Adolescent mothers aged 12-18 years and who watched television were less likely to delay breastfeeding initiation within the first hour of birth. Adolescent mothers who delivered at home (adjusted OR=2.63, 95% CI:1.86, 3.74) and made postnatal check-up after two days (adjusted OR=1.67, 95% CI: 1.21, 2.30) were significantly more likely to delay initiation breastfeeding within the first hour of birth. Younger infants, adolescent mothers living in Barisal region and who listened to radio reported increased odds of predominant breastfeeding and increased odds for bottle-feeding included male infants, an infant aged 0-5 months, Adolescent mothers who had eight or more antenatal clinic visits and richest wealth quintiles. In order for Bangladesh to meet the Sustainable Development Goals (SDGs) 2 and 3 by 2030, breastfeeding promotion programmes should discourage bottle-feeding among adolescent mothers from richest households and promote early initiation of breastfeeding especially among adolescent mothers who delivered at home and had late postnatal check-up after delivery

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro- in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with that from the PBPK model. The outcome from both the model pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates cAMP response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of NMDA receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood-brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.

Background: A Few preclinical studies have shown that Knee osteoarthritis (KOA) is linked to gut microbiome dysbiosis and chronic inflammation. This pilot study was designed to look at the gut microbiome composition in KOA patients and normal individuals with or without vitamin D deficiency (VDD, serum vitamin D <30 ng/ml). Methods: This pilot study was conducted prospectively in 24 participants. The faecal samples of all the participants were taken for DNA extraction. The V3-V4 region of 16s rRNA was amplified and the library was prepared and sequenced on the Illumina Miseq platform. Results: The mean (±SD) age was 45.5 (±10.2) years with no defined co-morbidities. Of 447 total Operational Taxonomic Units (OTUs), a differential abundance of 16 nominally significant OTUs between the groups were observed. Linear discriminate analysis (LEfSe) revealed a significant difference in bacteria among the study groups. Pseudobutyrivibrio and Odoribacter were specific for VDD while Parabacteroides, Butyricimonas, and Gordonibacter were abundant in the KOA_VDD group and Peptococcus, Intestimonas, Delftia, and Oribacterium were abundant in the KOA group. About 80% of bacterial species were common among different groups and hence labeled as core bacterial species. However, the core microbiome of KOA and VDD groups were not seen in the KOA_VDD group, suggesting that these bacterial groups were affected by the interaction of the KOA and VDD factors. Conclusion: Parabacteroides, Butyricimonas, Pseudobutyrivibrio, Odoribacter, and Gordonibacter are the predominant bacteria in vitamin D deficient patients with or without KOA. Together these results indicate an association between the gut microbiome, vitamin D, and knee osteoarthritis.

Background: Strong nursing faculty is paramount to promote disciplinary leadership and to prepare future nurses for practice. Our understanding of the factors associated with or predictive of nurse faculty retention and/or turnover is lacking. Purpose: The aim of this review is to identify and synthesize the existing literature on factors contributing to nurse faculty shortage in Canada and implications on nursing practice. Methods: A scoping review based on the Arskey and O’Malley’s five stage framework for scoping reviews was undertaken. Utilising the PRISMA protocol, a comprehensive and structured literature search was conducted in five databases of studies published in English.Findings: Limited through search inclusion and relevance of research, nine studies out of 220 papers met the criteria for this review and were thematically analyzed. Identified themes were: supply versus demand; employment conditions; organizational support; and personal factors.Discussion: Impending retirement of faculty, unsupportive leadership, and stressful work environments were frequently reported as significant contributing factors to the faculty shortage.Conclusions: This scoping review provide insights into how Canada’s schools of nursing could engage in grounded efforts to lessen nursing faculty shortage, both nationally and globally. We identified a gap in the literature that indicates that foundational work is needed to create context-specific solutions. The limited studies published in Canada suggests that this is a critical area for future research and funding.

A sufficient amount of tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥ 1 mm2) and tumor content rate (≥ 30%) on the success rate of Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm2 when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm2 with large EBUS-GS, and 1.81 ± 0.75 mm2 with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥ 1 mm2 was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS (n = 14), 93.4% (96.9%) for large EBUS-GS (n = 32), 62.5% (100%) for EBB (n = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm2 is adequate for samples to be tested with NGS.

We have previously demonstrated that the acute ingestion of essential amino acids may augment net protein balance in the elderly. Using a double blind, randomized controlled trial, our objective was to compare an experimental meal replacement enriched with essential amino acids (EMR) compared to a commercial meal replacement (Optifast®) provided once/day (q.d.) for four weeks on body composition and physical function in older, obese participants. Twenty-seven individuals (69±5 yrs; body mass index of 32±4 kg/m2) were randomly assigned to EMR (n=13) or Optifast® (n=15) supplementation. Measurements of body composition, skeletal muscle cross-sectional area (CSA), intrahepatic lipid and physical function were completed pre- and post-supplementation. Body mass, fat mass, and visceral fat mass were reduced with EMR but not altered with Optifast®. Thigh muscle CSA increased ( 4.1 ± 1.9 cm2, P = 0.03) with EMR but not Optifast®. There was a significant increase in the distance covered during the six-minute walk test with EMR ( 21±26 m) but no change in Optifast® ( 22±54 m). Improvements in body composition and physical function support the efficacious use of EMR-based meal replacements in the obese elderly.

The present study examined the volatile composition and antimicrobial and gastrointestinal activity of the essential oils of Elettaria cardamomum (L.) Maton harvested in India (EC-I) and Guatemala (EC-G). Monoterpene were present in higher concentration in EC-I (83.24%) than in EC-G (73.03%), whereas sesquiterpenes were present in higher concentration in EC-G (18.35%) than in EC-I (9.27%). Minimum inhibitory concentrations (MICs) of 0.5 and 0.1 mg/mL were demonstrated against Pseudomonas aeruginosa in EC-I and EC-G, respectively, whereas MICs of 0.125 and 1 mg/mL were demonstrated against Escherichia coli in EC-I and EC-G, respectively. The treatment with control had the highest kill-time potential, whereas the treatment with oils had shorter kill-time. EC-I was found to be more potent in the castor oil-induced diarrhoea model than EC-G. At 100 and 200 mg/kg, EC-I exhibited 40% and 80% protection, respectively, and EC-G exhibited 20% and 60% protection, respectively, in mice, whereas loperamide (positive control) exhibited 100% protection. In the in vitro experiments, EC-I inhibited both carbachol (CCh, 1 µM) and high K+ (80 mM)-induced contractions at significantly lower concentrations than EC-G. Thus, EC-I significantly inhibited P. aeruginosa and E. coli and exhibited more potent antidiarrheal and antispasmodic effects than EC-G.

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30 % of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Also, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

Background: Albumin has a pivotal role in the homeostasis of osmotic pressure and is associated with cardiovascular, nephrotic, hepatic, and nutritional diseases. The detection of hypoalbuminemia is a cornerstone for diagnosis of hidden diseases and patient deterioration. We developed and validated a deep-learning-based model (DLM) for detection of hypoalbuminemia using electrocardiography (ECG). Methods: This historical cohort study included data from consecutive patients from two hospitals. The patient data in one hospital were divided into development (82,499 ECGs from 54,248 patients) and internal validation (20,664 ECGs from 20,664 patients) datasets, whereas the patient data in the other hospital were included in only an external validation (37,421 ECGs from 37,421 patients) dataset. An DLM was developed using a 12-lead ECG signal, age, and sex from the development dataset. The endpoint was hypoalbuminemia, defined by serum albumin concentration below 3.5 g/dL. Results: During the internal and external validations, the areas under the receiver operating characteristic curve of the DLM for the detection of hypoalbuminemia were 0.887 (0.877–0.897) and 0.888 (0.880–0.896), respectively. Among the 27,400 individuals without hypoalbuminemia at the initial laboratory exam, those identified by the DLM as higher-risk patients had a significantly larger change in developing hypoalbuminemia than those in the low-risk group (7.09% vs. 1.01%, p < 0.001) during 24 months. The sensitivity map showed that the DLM focused on the T wave and QRS complex for the detection of hypoalbuminemia. Conclusions: The DLM exhibited a high accuracy for hypoalbuminemia detection and prediction using 12-, 6-, and single-lead ECGs.

To mitigate the COVID-19 infection, many world governments endorsed the cessation of non-essential activities, such as the school attendance. Thereby, forcing the evolution of the teaching model to the virtual classroom. In the present work we show the application of a modified version of the adapted COVID-19 stress scales (ACSS) which also included teaching anxiety and preparedness, and resilience for academic professionals in Mexico, during the unprecedented transformation of the education system undergone in the COVID-19 quarantine. Most of the studied variables: gender, age, academic degree, household occupants, having a disease, teaching level, teaching mode, work hours, resilience, teaching anxiety and preparedness, and fear of being an asymptomatic patient (FOBAP), showed significant statistical correlation between each other (p<0.050) and to the 6 areas of the ACSS (danger, contamination, social economical, xenophobia, traumatic stress and compulsive checking). Our results further showed that the perceived stress and anxiety, fell into the category of absent to mild with only the danger section of the ACSS falling into the moderate category. Finally, resilience generated throughout the quarantine, seems to be a predictor of the adaptation the academic professional has undergone to cope with stress.

(1) Introduction: The unprecedented coronavirus disease 2019 (COVID-19) epidemic has caused millions of infections worldwide and represents a significant challenge facing modern health care systems. This study was conducted to investigate the impact of lockdown measures on regional neonate services, which might be used to predict the long-term effects of medical behavior. (2) Methods: Using hospital information system (HIS) Statistics data from 4 January 2019 to 27 August 2020, an interrupted time-series analysis was employed to compare changes and trends in hospital admissions and disease spectrum before and after the lockdown interventions. Furthermore, this study was designed to evaluate whether the pandemic influenced newborns' healthcare behavior. (3) Results: Overall, 13,540 infants were admitted to the NICU during the pre-COVID period (n = 12082) and COVID-impacted period (n =4558). The patients' age at admission were younger than that of the pre-COVID-19 period (median age 5d vs. 6d after birth, p＜0.001). The overall number of neonate visits consistently decreased from the first days of the lockdown measures (24 January 2020). The disease spectrum for respiratory system, infectious diseases, and gastrointestinal disease indicated no declined immediately after intervention(p =0.079, p =0.113, p =0.060, respectively). There was an immediate decline in the volume of Jaundice-related conditions (p<0.001) after lockdown measures. The percentage of patients who suffer from respiratory system and infectious diseases has decreased (p =0.005 and p =0.002). However, a relatively high percentage of patients admitted to the neonatal intensive care unit (NICU) presented with Jaundice-related conditions (p <0.001). (4) Conclusions: In summary, the COVID-19 pandemic profoundly impacted the regional neonate services. However, it is still unclear what might be the effect of long-term effects from pandemic.

This review seeks to explain four features of viral respiratory illnesses that have perplexed many generations of microbiologists: (1) the seasonal occurrence of viral respiratory illness; (2) the occurrence of respiratory illness year-round in the Tropics; (3) the rapid response of illness to temperature drops in temperate regions; (4) the explosive arrival and rapid termination of epidemics caused by influenza and other respiratory viruses. I discuss the inadequacy of the popular explanations of seasonality, and propose a simple hypothesis, called Temperature Dependent Viral Tropism (TD-VT), that is compatible with the above and other features of respiratory illness. TD-VT notes that viruses can often transmit themselves more effectively if they moderate their pathogenicity (thereby maintaining the mobility of their hosts) and suggests that most endemic respiratory viruses accomplish this by developing thermal sensitivity, in the sense that they normally replicate rapidly only at temperatures below normal body temperature. This allows them to confine themselves to the upper respiratory tract and to avoid infecting the lungs, heart, gut etc. I review biochemical and tissue-culture studies that found that “wild” respiratory viruses often show natural thermal sensitivity within a range that supports organ-specific tropism within the human body, and I discuss the evident tendency for viral strains to adapt their thermal sensitivity to their local climate and season. I also explore the possible misinterpretation of early experiments where volunteers were inoculated nasally with viral samples and then chilled. Next, I discuss the practical implications of the TD-VT hypothesis for preventing and treating respiratory illness. Finally, I note that the hypothesis is very testable and make suggestions for the most important experiments to increase our understanding of the seasonality and pathogenicity of viral respiratory illness.

Neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyloidal lateral sclerosis (ALS), and Huntington disease (HD) are the most concerned disorders due to the lack of effective therapeutics and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, yet they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and ER-stress, which combats with stress conditions, but the overwhelming cellular stress response induces cell damage. Small molecules such as flavonoids could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the mechanistic ways of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

Rabies is endemic in southern Bhutan and children were reported to be the most frequent victims. We surveyed the knowledge, attitude, and practices on rabies among school children in three schools located in southern Bhutan. Descriptive statistics and logistic regression were performed to analyze the level of knowledge and variation of perception towards rabies among secondary school children. A total of 701 students (57.9% female, 42.1% male) had participated in the survey of which 98.2% heard about rabies. Most of the students demonstrated a good level of knowledge (59.7%) and a favorable perception towards rabies (57.7%). Multivariable logistic regression analysis revealed the importance of previous rabies awareness campaign increasing the likelihood of positive knowledge about rabies at the individual student and the school level. Similarly, higher grades of students’, employed mothers of the students, and students from villages were associated with more favorable perceptions. Overall, our study in rabies endemic areas of Southern Bhutan showed that most of the students have good knowledge and favorable perception towards rabies. However, we identified several knowledge gaps. Therefore, efforts should be made to address the knowledge gaps through regular awareness programs by actively engaging key stakeholders such as school-teachers and parents.

Background: Fetal overgrowth is related to many perinatal complications including stillbirth, cesarean section, maternal and neonatal injuries, and shoulder dystocia. It is related to maternal diabetes, obesity, and gestational weight gain, but also happens in low-risk pregnancies. There is ongoing discussion regarding definitions, methods of detection, and classification. The method used for detection is of crucial importance as it draws a line between those at risk and low-risk populations. Methods: In this a narrative review of relevant evidence identified through PubMed search with one of the general terms (macrosomia, large-for-gestational-age) combined with the outcome of interest. Results: This revive summarizes evidence on the relation of fetal overgrowth with stillbirth, cesarean sections, shoulder dystocia, anal sphincter injury, and hemorrhage. Customized growth charts help to detect mothers and fetuses at risk of those complications. Relations between fetal overgrowth and diabetes, maternal weight, and gestational weight gain. Conclusions: a substantial proportion of complications are an effect of the fetus growing above its potential and should be recognized as a new dangerous condition of Fetal Growth Acceleration

This study was conducted to investigate the correlations between social-emotional competence (SEC) and academic achievement (AA) among nursing students and to compare students’ level of each core skill of SEC (critical thinking disposition, self-directed learning, creativity, emotional intelligence, problem-solving, and collaboration) and academic achievement (clinical performance and subjective academic achievement). A cross-sectional design was adapted. Data were collected from 195 nursing students in the junior and senior years who had participated in clinical practicum from four universities in South Korea. General characteristics, levels of critical thinking disposition, self-directed learning, creativity, emotional intelligence, problem-solving, collaboration, and academic achievement were collected via self-reported questionnaire. Canonical correlation analysis was performed to evaluate the relationship between SEC and AA. The canonical correlation coefficient between SEC and AA was .762. Critical thinking disposition (Rs = .89), problem-solving (Rs = .86), cooperation (Rs = .80) made the most important contributions to SEC. Clinical performance (Rs=.95) and subjective AA (Rs=.57) were correlated with AA. SEC should be addressed to improve the AA of nursing students. All core skills of SEC should be regularly promoted. It is particularly urgent for nursing students to improve their creativity.

Local anaesthetic agents suppress action potentials in excitable tissues by blocking voltage-gated sodium channels. In doing so they inhibit the depolarisation of nociceptive nerve fibres and so prevent the transmission of pain impulses. UK legislation allows HCPC-registered Podiatrists with POM-A annotation access to six local anaesthetic drugs and two of these with the addition of adrenaline. The use of local anaesthetia has transformed the treatment of nail pathology by Podiatrists. In the UK, the drug of choice in podiatric practice is 3% mepivacaine hydrochloride: it is a good choice of drug for digital anaesthesia. This paper will review the chemistry, pharmacology and dose calculation of mepivacaine, and challenge some of the orthodoxy over the rigid calculation of maximum safe dosages.

Tarsal tunnel syndrome is a focal compressive neuropathy of the posterior tibial nerve or one of its associated branches. Brief mention is made in the literature of the use of corticosteroid injections for this condition. The basic technique of hydrodissection is used for other nerve entrapments and includes identifying the region of nerve compression, and the injection of a fluid medium to dissect between structures or fascial planes. We introduce our treatment protocol using a methylprednisolone/sterile water/ropivacaine hydrochloride injectate mix and peripheral nerve stimulation to a perform hydrodissection technique for tarsal tunnel syndrome.

Appropriate diagnostic testing to identify persons infected with SARS-COV-2 is a vital part of a health system’s ability to control the global pandemic of COVID-19 disease. The primary purpose of this review is to provide an overview of the mass testing strategy implemented throughout the UAE and the overall impact it has made on containing and controlling the spread of the disease. This study describes the mass testing strategy and capacity of the UAE during the pandemic of the new coronavirus SARS-COV-2. The UAE has conducted 15 million polymerase chain reaction (PCR) tests to SARS-COV-2, as of 15 November 2020. The number of tests per day varied from 10,000 by the end of March to 120,000 tests per day in November 2020. The mass testing initiative across the entire UAE forms an integral part of a bigger strategy focusing on testing, tracing contacts and isolating positive cases.

Background. Restoring large defects with proximal caries extending below the cemento-enamel junction and cavity margins located beneath the gingival tissues represents a very common clinical situation. The aim of this article is to propose a clinical classification of the localization subgingival margins of cavity.Material and methods. Diagnosis is carried out by periodontal probe perpendicular to the long axis of the tooth in the deepest point of the cavity’s margin. To describe the localization subgingival margins of cavity we use exponent which value is equal to the distance (integer number expressed in millimeters) of the level of epithelial attachment to the margin of the cavity. Three periodontal examiners, with >10 years of periodontal practice, were required to attend a calibration session aimed at the validation of the proposed classification. Results. The intrarater and interrater agreement among the localization subgingival margins of cavity: for intrarater agreement ranged from 0.74 to 0.95 (almost perfect agreement), whereas interrater agreement ranged from 0.26 to 0.59 (moderate agreement).Conclusions. The classification the localization subgingival margins of cavity is useful for reaching a more precise diagnosis.

Objective: To determine blood lead levels (BLL) in a healthy paediatric population and to analyse related sociodemographic, dietary and haematological factors. Methods: A cross-sectional study was made of 1,427 healthy subjects aged 1-16 years from the city of Almería (south-eastern Spain). BLL, iron parameters and erythropoietin were determined, and sociodemographic and dietary data obtained. The study data were analysed by multiple logistic regression. Results: The mean BLL was 1.98±1.1 µg/dl (95% CI:1.91–2.04). For 5.7% of the population, mean BLL was 2-5 µg/dl, for 2.1% it was >5 µg/dl and for 0.15% it was >10 µg/dl. Multivariate analysis showed that immigrant origin (OR:11.9; p<0.0001), low level of parental education (OR:4.6; p<0.02) and low dietary iron bioavailability (OR: 3.2; p<0.02) were all risk factors for toxic BLL. Subjects with toxic and non-toxic BLL presented similar iron and erythropoiesis-related parameters, except erythrocyte protoporphyrin, which was significantly higher in the BLL >5 µg/dl group. Conclusions: BLL and the prevalence of toxic BLL in healthy subjects aged 1-16 years living in south-eastern Spain are low and similar to those found in other developed countries. The factors associated with toxic BLL are immigrant origin, low level of parental education and dietary iron deficiency. The toxicity of BLL was not related to changes in the analytical parameters studied.

Given the high levels of overall volume of alcohol use, detrimental drinking patterns, and high levels of alcohol-attributable mortality and burden of disease, Lithuania implemented a series of alcohol control policies within a relatively short period of time (2008 to 2019). Based on their expected impact on alcohol consumption and alcohol-attributable harm, as well as their target population, the respective policies were classified using a set of objective criteria and expert opin-ion. The classification criteria included: positive vs. negative outcomes, mainly immediate versus delayed outcomes, and general population versus specific group outcomes. The judgement of the alcohol policy experts converged on the objective criteria, and, as a result, two tiers of inter-vention were identified: Tier 1 – general population interventions with an anticipated immediate impact; Tier 2 – other interventions aimed at the general population. In addition, interventions for specific populations were identified. This adaptable methodological approach to alcohol control policy classification is intended to provide guidance and support the evaluation of alcohol policies elsewhere, lay the foundation for the critical assessment of the respective policies to im-prove health and increase life expectancy, and to reduce crime and violence.

Mental health and emotional responses to the effects of COVID-19 lockdown in sub-Saharan Africa (SSA) are of serious public health concern and may negatively affect the mental health status of people. Hence, this study assessed the prevalence of mental health symptoms as well as emotional reactions among sub-Saharan Africans (SSAs) and associated factors among SSAs during the COVID-19 lockdown period. This was a web-based cross-sectional, a study on mental health and emotional features from 2005 respondents in seven SSA countries. This study was conducted between April 27 and May 17, 2020 corresponding to the lockdown period in most SSA countries. Respondents aged 18 years and above and the self-reported symptoms were feeling anxious, being worried, angry, bored and frustrated. These were the main outcomes and were treated as dichotomous variables. Univariate and multivariate logistic regression analyses were used to identify the factors associated with these symptoms. We found that over half (52.2%) of the participants reported any of the mental health symptoms in SSA and the prevalence of feeling bored was 70.5% followed by feeling anxious (59.1%), being worried (57.5%), frustrated (51.5%) and angry (22.3%) during the COVID-19 pandemic. Multivariate analysis revealed that males, those aged >28 years, Central and Southern Africans, those who were not married, the unemployed, those living with more than six persons in a household, had higher odds of mental health and emotional symptoms. Similarly, people who perceived low risk of contracting the infection, and those who thought the pandemic would not continue after the lockdown had higher odds of mental health and emotional symptoms. Health care workers had lower odds for feeling angry than non-healthcare workers. During COVID-19 lockdown periods in SSA, about one in two participants reported mental health and emotional symptoms. Public health measures can be effectively used to identify target groups for prevention and treatment of mental health and emotional symptoms. Such interventions should be an integral component of SSA governments’ response and recovery strategies of any future pandemic.

Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.

The utilization of person centered care is highlighted as essential for health promotion, yet implementation has been inconsistent and multiple issues remain. There is a dearth of applied re-search exploring the facets of successful implementation. In this paper, a person centered wellbeing program spanning various groups is discussed outlining the central principles that have allowed for successful outcomes. The main data emerges from 10 years of pragmatic pre-post service evaluation. Measures of functional capacity and wellbeing were captured using validated measures. The method for this paper is a narrative exploration of the theory and practices that can explain the continual improvement the clinics have achieved over 10 years. Core principles relate to connecting with people, connecting through groups, and connecting with self. The operationalization and theoretical explanation of these principles is outlined alongside 10 years of data which shows sustained improvement in a range of outcomes. The discussion of these principles posits essential factors to prioritize to advance the implementation of person centered care in health promotion for long term conditions.

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1α staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring Programme, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related hepatitis but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild hepatitis. Mean age for the cases was 45.7 years, 4(26.7%) were women and 5(33.34%) were children under 18 years, of them 3(20%) were fatal. Polytherapy with other antiepileptic drugs (p=0.047) and alcohol consumption (p<0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p<0.001). The cases developed hepatocellular hepatitis (p<0.001), while the mild hepatitis controls had a higher rate of cholestatic hepatitis (p<0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p= 0.033 and p=0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

Background and Objectives: The IPED study showed that a smartphone-based event recorder increased the number of patients in whom an ECG was captured during symptoms over five-fold to more than 55% at 90 days compared to standard care [1] and concluded that this safe, non-invasive and easy to use device should be considered part of on-going care to all patients presenting acutely with unexplained palpitations or pre-syncope. This study reports the process of establishing a smartphone palpitation and pre-syncope service. Materials and Methods: A clinical Standard Operating Procedure (SOP) was devised, and funding was secured through a business case for the purchase of 40 AliveCor devices in the first instance. The clinic was launched on 22nd July 2019. Results: Between 22nd July 2019 and 31st October 2019, 68 patients seen in the ED with palpitations or pre-syncope were referred to SPACC. 30 were male and 38 female and mean age was 45.8 (SD 15.1) with a range from 18 to 80 years. 50 (74%) patients underwent full investigation. 7 (11%) patients were deemed on first assessment to have non-cardiac palpitations and were not fitted with the device. All patients who underwent full investigation achieved symptomatic rhythm correlation most with sinus rhythm, ventricular ectopics or bigeminy. A symptomatic cardiac dysrhythmia was detected in 6 (8.8%) patients. 3 patients had supraventricular tachycardia; SVT (4%), 2 had atrial fibrillation (3%) and 1 atrial flutter (2%). Qualitative feedback from the SPACC team suggested several areas where improvement to the clinic could be made. Conclusion: We believe a smartphone palpitation service based in ambulatory care is simple to implement and is effective at detecting cardiac dysrhythmia in ED palpitation patients.

Controlling Nutritional Status (CONUT) Score is useful for the nutritional screening. We aimed to explore whether the CONUT score may predict a 3-month functional outcome in hemorrhagic stroke (AHS). Totally, 349 patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. Poor functional outcomes were defined as the modified Rankin Scale (mRS) score of ≥ 3 at 3 months. A total of 328 patients (mean age, 60.4 ± 12.83 years; 66.8% male) were included, 172 (52.40%) patients at malnutrition risk and 104 (31.7%) patients with a poor prognosis. High-CONUT patients had lower total lymphocyte counts and total cholesterol levels than low-CONUT patients (p &lt; 0.001 and p = 0.012). At 3-month post discharge, patients with malnutrition risk had higher hospitalization costs (p = 0.021), lower Barthel Index (p = 0.001), and more infectious complications (p = 0.002) than those without, and there was a greater risk for poor functional outcomes in the high-CONUT compared with the low-CONUT patients at admission (adjusted odds ratio: 2.32, 95% confidence interval: 1.28-4.17). High-CONUT scores predict a 3-month poor prognosis in AHS, which may help identify the AHS patients who need additional nutritional managements.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Identifying the SARS-CoV-2 virus has been a unique challenge for the scientific community. In this paper, we discuss a practical solution to help guide clinicians with interpretation of the probability that a positive, or negative, COVID-19 test result indicates an infected person, based on their clinical estimate of pre-test probability of infection.The authors conducted a small survey on LinkedIn to confirm that hypothesis that that the clinical pre-test probability of COVID-19 increases relative to local prevalence of disease plus patient age, known contact, and severity of symptoms. We examined results of PPA (Positive Percent Agreement, sensitivity) and NPA (Negative Percent Agreement, specificity) from 73 individual laboratory experiments for molecular tests for SARS-CoV-2 as reported to the FIND database ¹, and for selected methods in FDA EUA submissions^2,3. Authors calculated likelihood ratios to convert pre-test to post-test probability of disease and designed an online calculator to create graphics and text to report results. Despite best efforts, false positive and false negative Covid-19 test results are unavoidable^4,5. A positive or negative test result from one laboratory has a different probability for the presence of disease than the same result from another laboratory. Likelihood ratios and confidence intervals can convert the physician or other healthcare professional’s clinical estimate of pre-test probability to post-test probability of disease. Ranges of probabilities differ depending on proven method PPA and NPA in each laboratory. We recommend that laboratories verify PPA and NPA and utilize a the “Clinician’s Probability Calculator” to verify acceptable test performance and create reports to help guide clinicians with estimation of post-test probability of COVID-19.

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

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

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

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

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

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

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

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

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

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

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