A Mechanism for the Activation of the Influenza Virus Transcriptase.

Influenza virus RNA polymerase (FluPol), a heterotrimer composed of PB1, PB2, and PA subunits (P3 in influenza C), performs both transcription and replication of the viral RNA genome. For transcription, FluPol interacts with the C-terminal domain (CTD) of RNA polymerase II (Pol II), which enables FluPol to snatch capped RNA primers from nascent host RNAs. Here, we describe the co-crystal structure of influenza C virus polymerase (FluPolC) bound to a Ser5-phosphorylated CTD (pS5-CTD) peptide. The position of the CTD-binding site at the interface of PB1, P3, and the flexible PB2 C-terminal domains suggests that CTD binding stabilizes the transcription-competent conformation of FluPol. In agreement, both cap snatching and capped primer-dependent transcription initiation by FluPolC are enhanced in the presence of pS5-CTD. Mutations of amino acids in the CTD-binding site reduce viral mRNA synthesis. We propose a model for the activation of the influenza virus transcriptase through its association with pS5-CTD of Pol II.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.

BACKGROUND AND AIMS: Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis. METHODS: The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model. RESULTS: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (ß = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways. CONCLUSIONS: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

The EU's GM crop conundrum: Did the EU policy strategy to convert EFSA GMO guidance into legislation deliver on its promises?: Did the EU policy strategy to convert EFSA GMO guidance into legislation deliver on its promises?

Efforts by the EU to improve its regulatory framework for importing GM food and feed have done nothing to make the process easier and more predictable for applicants.

GEnZ explorer: a tool for visualizing agroclimate to inform research and regulatory risk assessment.

Confined field trials (CFT) of genetically engineered (GE) crops are used to generate data to inform environmental risk assessments (ERA). ERAs are required by regulatory authorities before novel GE crops can be released for cultivation. The transportability of CFT data to inform risk assessment in countries other than those where the CFT was conducted has been discussed previously in an analysis showing that the primary difference between CFT locations potentially impacting trial outcomes is the physical environment, particularly the agroclimate. This means that data from trials carried out in similar agroclimates could be considered relevant and sufficient to satisfy regulatory requirements for CFT data, irrespective of the country where the CFTs are conducted. This paper describes the development of an open-source tool to assist in determining the transportability of CFT data. This tool provides agroclimate together with overall crop production information to assist regulators and applicants in making informed choices on whether data from previous CFTs can inform an environmental risk assessment in a new country, as well as help developers determine optimal locations for planning future CFTs. The GEnZ Explorer is a freely available, thoroughly documented, and open-source tool that allows users to identify the agroclimate zones that are relevant for the production of 21 major crops and crop categories or to determine the agroclimatic zone at a specific location. This tool will help provide additional scientific justification for CFT data transportability, along with spatial visualization, to help ensure regulatory transparency.

Underwater versus conventional EMR of large nonpedunculated colorectal lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Underwater EMR (UEMR) is an alternative procedure to conventional EMR (CEMR) to treat large, nonpedunculated colorectal lesions (LNPCLs). In this multicenter, randomized controlled clinical trial, we aimed to compare the efficacy and safety of UEMR versus CEMR on LNPCLs. METHODS: We conducted a multicenter, randomized controlled clinical trial from February 2018 to February 2020 in 11 hospitals in Spain. A total of 298 patients (311 lesions) were randomized to the UEMR (n = 149) and CEMR (n = 162) groups. The main outcome was the lesion recurrence rate in at least 1 follow-up colonoscopy. Secondary outcomes included technical aspects, en bloc resection rate, R0 resection rates, and adverse events, among others. RESULTS: There were no differences in the overall recurrence rate (9.5% UEMR vs 11.7% CEMR; absolute risk difference, -2.2%; 95% CI, -9.4 to 4.9). However, considering polyp sizes between 20 and 30 mm, the recurrence rate was lower for UEMR (3.4% UEMR vs 13.1% CEMR; absolute risk difference, -9.7%; 95% CI, -19.4 to 0). The R0 resection showed the same tendency, with significant differences favoring UEMR only for polyps between 20 and 30 mm. Overall, UEMR was faster and easier to perform than CEMR. Importantly, the techniques were equally safe. CONCLUSIONS: UEMR is a valid alternative to CEMR for treating LNPCLs and could be considered the first option of treatment for lesions between 20 and 30 mm due to its higher en bloc and R0 resection rates. (Clinical trial registration number: NCT03567746.).

Sensorimotor, cognitive and affective behavior according to perceived level of disability in patients with chronic low back pain: an observational cross-sectional study.

OBJECTIVES: The aim was to evaluate the influence of the level of disability on sensorimotor and psychological variables in nonspecific chronic low back pain (NCLBP). METHODS: A cross-sectional observational study was performed with 90 participants, divided into one group with NCLBP (60 participants) and one asymptomatic group (30 participants). Symptomatic participants were divided into a "major" or "minor" disability group using the Roland Morris Disability Questionnaire score, resulting in two groups of 30 participants. All participants completed a series of self-administered questionnaires and performed sensorimotor tests. RESULTS: There were no statistically significant differences in the sensorimotor variables except in pain intensity, which was greater in the NCLBP group with high lumbar disability. There were statistically significant differences between the symptomatic groups in the degree of self-efficacy, pain catastrophism and kinesiophobia. CONCLUSIONS: Patients with NCLBP and high levels of disability present greater pain intensity and significantly poorer results in psychological variables compared with those with NCLBP and low levels of disability. In contrast, there were no differences for sensorimotor variables between the patients with NCLBP and high levels of disability and those with low levels of disability.

WHO method for estimating congenital syphilis to inform surveillance and service provision, Paraguay.

Problem: In Paraguay, incomplete surveillance data resulted in the burden of congenital syphilis being underestimated, which, in turn, led to missed opportunities for infant diagnosis and treatment. Approach: The prevalence of congenital syphilis, as defined by the World Health Organization (WHO), was estimated for Paraguay using the WHO congenital syphilis estimation tool. This tool was also used to monitor progress towards the elimination of mother-to-child transmission of syphilis. Local setting: The burden of syphilis in Paraguay has historically been high: its prevalence in pregnant women was estimated to be 3% in 2018. Relevant changes: The incidence rate of congenital syphilis estimated using the WHO tool was around nine times the reported prevalence. Subsequently, Paraguay: (i) provided training to improve diagnosis and case reporting; (ii) strengthened information systems for case monitoring and reporting; and (iii) procured additional rapid dual HIV-syphilis and rapid plasma reagin tests to increase syphilis testing capacity. In addition, the Ministry of Health prepared a new national plan for eliminating mother-to-child transmission of syphilis, with clear monitoring milestones. Lessons learnt: Health-care providers' reporting and surveillance procedures for congenital syphilis may not adequately reflect national and international case definitions. Use of the WHO congenital syphilis estimation tool in Paraguay drew attention to congenital syphilis as a national public health problem and highlighted the importance of comprehensive national surveillance systems and accurate data. Ongoing use of the WHO tool can track progress towards the elimination of mother-to-child transmission of syphilis by helping improve syphilis service coverage and national surveillance.

Persistent trigeminal artery associated with an occipital arteriovenous malformation: a case report and literature review.

BACKGROUND: Persistent trigeminal artery or persistent primitive trigeminal artery (PTA) is the most common carotid-basilar anastomosis in both cadaveric and live patient studies, followed by persistent hypoglossal and persistent otic arteries. Approximately 0.2% of all angiographies reported this finding. CASE REPORT: We present the case of a 21-year-old male who arrived at the emergency department with tonic‒clonic seizures. After performing diagnostic contrast magnetic resonance imaging and digital subtraction angiography, the patient was diagnosed with a right occipital arteriovenous malformations (AVM) fed by the right calcarine artery associated with an ipsilateral PTA. After considering surgical and endovascular treatment options, the patient was selected for watchful waiting. We included a literature review of the PTA, the results of a PubMed search regarding the combined presence of these findings, and a brief discussion providing insight into the implications for treatment. CONCLUSIONS: Although several studies have linked PTA to different vascular pathologies, such as cerebral aneurysms, the association between PTA and AVMs remains scarce. This case, along with the literature review, shows that further research is needed to characterize the relationship between these findings.

Cyber-Physical Vulnerability Assessment in Smart Grids Based on Multilayer Complex Networks.

In the last decade, the main attacks against smart grids have occurred in communication networks (ITs) causing the disconnection of physical equipment from power networks (OTs) and leading to electricity supply interruptions. To deal with the deficiencies presented in past studies, this paper addresses smart grids vulnerability assessment considering the smart grid as a cyber-physical heterogeneous interconnected system. The model of the cyber-physical system is composed of a physical power network model and the information and communication technology network model (ICT) both are interconnected and are interrelated by means of the communication and control equipment installed in the smart grid. This model highlights the hidden interdependencies between power and ICT networks and contains the interaction between both systems. To mimic the real nature of smart grids, the interconnected heterogeneous model is based on multilayer complex network theory and scale-free graph, where there is a one-to-many relationship between cyber and physical assets. Multilayer complex network theory centrality indexes are used to determine the interconnected heterogeneous system set of nodes criticality. The proposed methodology, which includes measurement, communication, and control equipment, has been tested on a standardized power network that is interconnected to the ICT network. Results demonstrate the model's effectiveness in detecting vulnerabilities in the interdependent cyber-physical system compared to traditional vulnerability assessments applied to power networks (OT).

Extracellular galectins as controllers of cytokines in hematological cancer.

Galectins and cytokines are both secreted proteins whose levels are prognosis factors for several cancers. Extracellular galectins bind to the glycans decorating glycoproteins and are overproduced in most cancers. Accumulative evidence shows that galectins regulate cytokines during cancer progression. Although galectins alter cytokine function by binding to the glycans decorating cytokines or their receptors, cytokines could also regulate galectin expression and function. This review revises these complex interactions and their clinical impact, particularly in hematological cancers.

Auditory and visual distraction improve muscle endurance: a randomised controlled trial.

The main aim was to investigate the influence of various distracting stimuli on the endurance-strength and fatigue of the lumbar region in asymptomatic participants. Fifty-four healthy individuals were randomised to three groups: auditory distraction group (ADG), visual distraction group (VDG) and control group without distraction (CG). Lumbar muscle endurance and perceived fatigue were the outcome measures. Lumbar muscle endurance was assessed with the Biering-Sorensen test, and perceived fatigue was assessed with the modified Borg scale, once baseline and second with the distraction intervention. Lumbar muscle endurance showed significant changes over time, and there were intragroup differences for VDG and ADG. The direct comparison did show significant differences between both distraction groups with respect to the control group with a large effect size (ΔVDG-CG: p < 0.001, d = 1.55 and, ΔADG-CG: p = 0.008, d = 1.07) but not between the two distraction groups (ΔVDG-VDG: p = 0.56). Fatigue showed significant changes over time but not for group*time interaction, revealing intragroup differences for VDG and ADG. There were no intragroup differences in the CG for muscle resistance or fatigue, and there were no between-group differences. Auditory and visual distractors might produce a significant increase in muscle resistance during the Biering-Sorensen test. Both techniques are valid for increasing lumbar muscle endurance but also both stimuli produced a higher level of fatigue or perception of effort once the test was completed when compared with CG. Finally, we were unable to demonstrate that one type of stimulus produces superior results to the other.

Smart Sensors for Smart Grid Reliability.

Sensors for monitoring electrical parameters over an entire electricity network infrastructure play a fundamental role in protecting smart grids and improving the network's energy efficiency. When a short circuit takes place in a smart grid it has to be sensed as soon as possible to reduce its fault duration along the network and to reduce damage to the electricity infrastructure as well as personal injuries. Existing protection devices, which are used to sense the fault, range from classic analog electro-mechanics relays to modern intelligent electronic devices (IEDs). However, both types of devices have fixed adjustment settings (offline stage) and do not provide any coordination among them under real-time operation. In this paper, a new smart sensor is developed that offers the capability to update its adjustment settings during real-time operation, in coordination with the rest of the smart sensors spread over the network. The proposed sensor and the coordinated protection scheme were tested in a standard smart grid (IEEE 34-bus test system) under different short circuit scenarios and renewable energy penetration. Results suggest that the short-circuit fault sensed by the smart sensor is improved up to 80% and up to 64% compared with analog electromechanics relays and IEDs, respectively.

Physiotherapy Based on a Biobehavioral Approach with or Without Orthopedic Manual Physical Therapy in the Treatment of Nonspecific Chronic Low Back Pain: A Randomized Controlled Trial.

OBJECTIVE: To compare the effectiveness of a biobehavioral approach with and without orthopedic manual physical therapy on the intensity and frequency of pain in patients diagnosed with nonspecific chronic low back pain. METHODS: A single-blind randomized controlled trial. Fifty patients were randomly allocated into two groups: one group received biobehavioral therapy with orthopedic manual physical therapy, and the other group received only biobehavioral therapy. Both groups completed a total of eight sessions, with a frequency of two sessions per week. The somatosensory, physical, and psychological variables were recorded at baseline and during the first and third month after initiation of treatment. RESULTS: In both groups, the treatment was effective, presenting significant differences for all the variables in the time factor. There were no significant differences between groups in intensity or frequency of pain, with a large effect size (>0.80), but there were intragroup differences for both intervention groups at one- and three-month follow-up. There were also no significant differences between groups in the secondary variables during the same follow-up period. CONCLUSIONS: The results of this study suggest that orthopedic manual physical therapy does not increase the effects of a treatment based on biobehavioral therapy in the short or medium term, but these results should be interpreted with caution.

An assessment of bacterial overgrowth and translocation in the non-alcoholic fatty liver of patients with morbid obesity.

BACKGROUND: small intestinal bacterial overgrowth (SIBO) and bacterial translocation across the intestinal wall have been allegedly associated with non-alcoholic fatty liver (NAFL). Our goal was to study such alleged association in morbidly obese patients. PATIENTS AND METHODS: patients with morbid obesity were consecutively included prior to bariatric surgery. Exclusion criteria included normal liver biopsy, other causes of liver disease, and duodenal mucosal atrophy. A gastroscopy was performed for duodenal aspirate culture and duodenal biopsy, and peripheral venous blood was drawn to assess lipopolysaccharide (LPS) and LPS-binding protein (LBP) levels. A liver biopsy was carried out during surgery. RESULTS: seventy-one patients were included; 26 were excluded because of normal liver biopsy. Forty-five had NAFL. Eighteen were male, mean age was 45.8 years (22-69), and BMI was 47.8 kg/m2 (37-58). A total of 25% had SIBO in their duodenal aspirate culture. There was statistical significance for the association of LBP levels and SIBO with steatosis grade (p < 0.05 and p = 0.077, respectively). There was no statistical association with non-alcoholic steatohepatitis (NASH) index, but a trend towards association was found. LPS levels were not associated with steatosis grade or NASH index. CONCLUSIONS: the higher the grade of liver steatosis, the higher were the circulating LBP levels and SIBO rates seen in patients with morbid obesity and NAFL.

Short and long-term outcomes of underwater EMR compared to the traditional procedure in the real clinical practice.

BACKGROUND AND AIMS: underwater endoscopic mucosal resection (U-EMR) has been recently described as an alternative to endoscopic mucosal resection (EMR) for flat colorectal polyps. However, the real applications remain unclear due to the lack of comparative studies. METHODS: a multi-centric prospective study was performed from November 2016 to December 2017. All lesions larger than 15 mm that were resected with both techniques were included in the study. The samples were matched using the size, morphology, site and access (SMSA) score as a reference. The efficacy, efficiency and adverse events rates were compared. RESULTS: a total of 162 resections were collected (112 EMR and 50 U-EMR) with an average size of 25 mm. U-EMR achieved better results for the en bloc resection rate (49 vs 62%; p = 0.08) and there were no cases of an incomplete resection (10.7 vs 0%; p = 0.01). U-EMR was faster than EMR and there were no differences in the adverse events rate. Furthermore, U-EMR tended to achieve better results in terms of recurrence. Performing the resection in emersion appeared to prevent the cautery artefact, especially in sessile serrated adenomas. CONCLUSION: in the real clinical practice, U-EMR and EMR are equivalent in terms of efficacy and safety. Furthermore, U-EMR may be a feasible approach to prevent cautery artefact, allowing an accurate pathologic assessment.

A retrospective and prospective 12-month observational study of the socioeconomic burden of moderate to severe irritable bowel syndrome with constipation in Spain.

INTRODUCTION: The socioeconomic burden of irritable bowel syndrome with constipation (IBS-C) has never been formally assessed in Spain. PATIENTS AND METHODS: This 12-month (6-month retrospective and prospective periods) observational, multicentre study assessed the burden of moderate-to-severe IBS-C in Spain. Patients were included if they had been diagnosed with IBS-C (Rome III criteria) within the last 5 years and had moderate-to-severe IBS-C (IBS Symptom Severity Scale score [IBS-SSS] ≥175) at inclusion. The primary objective was to assess the direct cost to the Spanish healthcare system (HS). RESULTS: A total of 112 patients were included, 64 (57%) of which had severe IBS-C at inclusion. At baseline, 89 (80%) patients reported abdominal pain and distention. Patient quality of life (QoL), measured by the IBS-C QoL and EQ-5D instruments, was found to be impaired with a mean score of 59 and 57 (0-100, worst-best), respectively. Over the 6-month prospective period the mean IBS-C severity, measured using the IBS-SSS showed some improvement (315-234 [0-500, best-worst]). During the year, 89 (80%) patients used prescription drugs for IBS-C, with laxatives being the most frequently prescribed (n=70; 63%). The direct cost to the HS was €1067, and to the patient was €568 per year. The total direct cost for moderate-to-severe IBS-C was €1635. DISCUSSION: The majority of patients reported continuous IBS-C symptoms despite that 80% were taking medication to treat their IBS-C. Overall healthcare resource use and direct costs were asymmetric, with a small group of patients consuming the majority of resources.

Somatosensory and Motor Differences between Physically Active Patients with Chronic Low Back Pain and Asymptomatic Individuals.

Background and Objectives: Chronic low back pain (CLBP) is the most common occupational disorder due to its associated disability and high risk of recurrence and chronicity. However, the mechanisms underlying physical and psychological variables in patients with CLBP remain unclear. The main objective of this study was to assess whether there were differences between physically active patients with nonspecific CLBP compared with asymptomatic individuals in sensorimotor and psychological variables. Materials and Methods: This was an observational cross-sectional design with a nonprobabilistic sample. The sample was divided into two groups: individuals with nonspecific CLBP (n = 30) and asymptomatic individuals as a control (n = 30). The psychological variables assessed were low back disability, fear of movement, pain catastrophizing, and self-efficacy. The sensorimotor variables assessed were two-point discrimination, pressure pain threshold, lumbopelvic stability, lumbar flexion active range of motion, and isometric leg and back strength. Results: Statistically significant differences between the groups in terms of catastrophizing levels (p = 0.026) and fear of movement (p = 0.001) were found, but no statistically significant differences between groups were found in self-efficacy (p > 0.05). No statistically significant differences between the groups in any of the sensorimotor variables were found (p > 0.05). Conclusion: No sensorimotor differences were found between patients with asymptomatic and chronic low back pain, but differences were found in the psychological variables of catastrophizing and fear of movement.

Prevalence and incidence estimates for syphilis, chlamydia, gonorrhea, and congenital syphilis in Colombia, 1995-2016.

OBJECTIVES: To estimate adult (15-49 years old) prevalence and incidence of active syphilis, gonorrhea, and chlamydia, and incidence of congenital syphilis (CS) and adverse birth outcomes (ABOs) in Colombia, over 1995-2016. METHODS: The Spectrum-STI epidemiological model tool estimated gonorrhea and chlamydia prevalences as moving averages across prevalences observed in representative general population surveys. For adult syphilis, Spectrum-STI applied segmented polynomial regression through prevalence data from antenatal care (ANC) surveys, routine ANC-based screening, and general population surveys. CS cases and ABOs were estimated from Spectrum's maternal syphilis estimates and proportions of women screened and treated for syphilis, applying World Health Organization case definitions and risk probabilities. RESULTS: The Spectrum model estimated prevalences in 2016 of 0.70% (95% confidence interval (CI): 0.15%-1.9%) in women and 0.60% (0.1%-1.9%) in men for gonorrhea and of 9.2% (4.4%-15.4%) in women and 7.4% (3.5%-14.7%) in men for chlamydia, without evidence for trends over 1995-2016. The prevalence of active syphilis in 2016 was 1.25% (1.22-1.29%) in women and 1.25% (1.1%-1.4%) in men, decreasing from 2.6% (2.1%-3.2%) in women in 1995. Corresponding CS cases in 2016 (including cases without clinical symptoms) totaled 3 851, of which 2 245 were ABOs. Annual CS and ABO estimates decreased over 2008-2016, reflecting decreasing maternal prevalence and increasing cases averted through ANC-based screening and treatment. CONCLUSIONS: The available surveillance and monitoring data synthesized in Spectrum-STI- and the resulting first-ever national STI estimates for Colombia-highlighted Colombia's persistently high STI burden. Adult syphilis and congenital syphilis are estimated to be falling, reflecting improving screening efforts. Strengthened surveillance, including with periodic screening in low-risk populations and future refined Spectrum estimations, should support planning and implementation of STI prevention and control, including CS elimination.

Endoscopic submucosal hydro-dissection as a rescue treatment of a large recurrent lateral spreading tumor in an ileorectal anastomosis.

BACKGROUND: subtotal colectomy with ileorectal anastomosis (IRA) is currently the most common surgical option in young patients with familial adenomatous polyposis (FAP). However, this surgery does prevent the appearance of lesions in the rectal remnant. In these cases, the endoscopic submucosal dissection might be a feasible option. However, drawbacks such as extreme fibrosis and a difficult maneuverability in the rectal remnant make this technique rather challenging. An ESD by the pocket creation method was planned with the purpose of overcoming these handicaps. CASE REPORT: an en-bloq resection of 30 mm of the recurrent adenoma located in rectal remnant of a 42-year-old woman with FAP was successfully achieved following this approach. Two months of follow up endoscopy did not show residual adenomatous tissue. DISCUSSION: in summary, endoscopic submucosal dissection by the pocket creation method allowed a safe and effective dissection and an en-bloc resection of this challenging polyp was achieved.