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Nanoparticles include particles ranging in size from nanometers to micrometers, whose physicochemical characteristics are optimized to make them appropriate delivery vehicles for drugs or immunogens important in the fight and/or prevention of infectious diseases. There has been a rise in the use of nanoparticles in preventive vaccine formulations as immunostimulatory adjuvants, and as vehicles for immunogen delivery to target immune cells. Toxoplasma is important worldwide, and may cause human toxoplasmosis. In immunocompetent hosts, infection is usually asymptomatic, but in immunocompromised patients it can cause serious neurological and ocular consequences, such as encephalitis and retinochoroiditis. Primary infection during pregnancy may cause abortion or congenital toxoplasmosis. Currently, there is no effective human vaccine against this disease. Evidence has emerged from several experimental studies testing nanovaccines showing them to be promising tools in the prevention of experimental toxoplasmosis. For the present study, a literature review was carried out on articles published over the last 10 years through the PubMed database, pertaining to in vivo experimental models of T. gondii infection where nanovaccines were tested and protection and immune responses evaluated. This review aims to highlight the way forward in the search for an effective vaccine for toxoplasmosis.

Regional anesthesia (RA) has several benefits and its use has increased with the advent of ultrasound-guided techniques. Opioid-sparing anesthesia and reduced use of general anesthesia are some of the mainstay advantages of RA. Although anesthetic practices differ deeply between countries, RA has assumed a crucial role in the daily practice of anesthesiologists, particularly during the COVID-19 pandemic period. This cross-sectional study provides an overview of peripheral nerve block (PNB) techniques performed in Portuguese hospitals. An online survey was reviewed by members of Clube de Anestesia Regional (CAR/ESRA Portugal) and then sent to a national mailing list of anesthesiologists. The survey focused on specific topics related to RA techniques such as the importance of training and experience, and the relevance of logistical limitations during the execution of RA. All data were collected anonymously and included in a Microsoft Excel (Microsoft Corp., Redmond, WA, USA) database, for further analysis. A total of 335 valid answers were obtained. All participants considered RA as a key competence in their daily practice. Half of those inquired performed PNB techniques once to twice per week. The main limitations identified for performing RA in Portuguese hospitals were the absence of block rooms and insufficiently trained personnel for the appropriate and safe execution of these techniques. This survey provides a comprehensive overview of RA in the Portuguese setting and could serve as a baseline for further studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Teixeira et al.)

Oral hygiene has been shown to reduce adverse events and promote the quality of life of patients with stroke. However, a stroke can result in the impairment of physical, sensory, and cognitive abilities, and comprise self-care. Although nurses recognize its benefits, there are areas for improvement in the implementation of the best evidence-based recommendations. The aim is to promote compliance with the best evidence-based recommendations on oral hygiene in patients with stroke. This project will follow the JBI Evidence Implementation approach. The JBI Practical Application of Clinical Evidence System (JBI PACES) and the Getting Research into Practice (GRiP) audit and feedback tool will be used. The implementation process will be divided into three phases: (i) establishing a project team and undertaking the baseline audit; (ii) providing feedback to the healthcare team, identifying barriers to the implementation of best practices, and co-designing and implementing strategies using GRIP, and (iii) undertaking a follow-up audit to assess the outcomes and plan for sustainability. So, the successful adoption of the best evidence-based recommendations on oral hygiene in patients with stroke will reduce the adverse events related to poor oral care and may improve patients' quality of care. This implementation project has great transferability potential to other contexts.

The anticancer activity of epigallocatechin-3-gallate (EGCG), orally administrated, is limited by poor bioavailability, absorption, and unpredictable distribution in human tissues. EGCG charged nanoparticles may represent an opportunity to overcome these limitations. We assayed two different kinds of lipid nanoparticles (LNPs and LNPs functionalized with folic acid) charged with EGCG on three breast carcinoma cell lines (MCF-7, MDA-MB-231, and MCF-7TAM) and the human normal MCF10A mammary epithelial cells. Both LNPs loaded with EGCG, at low concentrations, induced a significant cytotoxicity in the three breast carcinoma cells but not in MCF10A cells. In view of a future application, both LNPs and LNPs-FA were found to be very suitable for in vitro studies and useful to improve EGCG administration in vivo . Since they are produced by inexpensive procedures using bioavailable, biocompatible, and biodegradable molecules, they represent an applicable tool for a more rationale use of EGCG as an anti-cancer agent., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Metabolic-associated fatty liver disease (MAFLD) is an increasingly prevalent cause of chronic liver disease. In 2020, the FibroScan-AST (FAST) score was internationally validated as a new tool able to identify patients with steatohepatitis who benefit the most from further therapies, based on liver transient elastography (LTE) findings and serum levels of aspartate aminotransferase (AST). We aimed to identify, in MAFLD patients, which metabolic features may predict a higher FAST score., Methods: Retrospective study of consecutive patients with MAFLD submitted to LTE for two consecutive years. Patients without an AST sample collected within 6 months of the LTE were excluded. FAST score was calculated, stratifying the patient's risk as low (<0.35), medium (0.35-0.67), or high (>0.67)., Results: The sample included 117 patients, 53.0% of the female gender, with a mean age of 53 years. On multivariate analysis, patients with type 2 diabetes (T2DM) ( p < 0.001), dyslipidemia ( p = 0.046), and smoking habits ( p = 0.037) presented with significantly higher FAST score values. Furthermore, diabetic patients did not only present significantly higher FAST scores but were also more frequently assigned to the high-risk group according to FAST score criteria (OR = 9.2; 95% CI = 1.8-45.5; p = 0.007)., Conclusions: Calculating the FAST score, patients with T2DM presented a significantly higher risk of having significant fibrosis and steatohepatitis. Physicians may rely on this validated instrument to more easily identify which patients with T2DM and MAFLD benefit the most from a specialized follow-up., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A 2A receptors (A 2A R) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A 2A R to MF sprouting. A 2A R blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A 2A R located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A 2A R to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A 2A R should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A 2A R contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A 2A R to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A 2A R axis as a regulator of circuit remodeling in the mature brain., (© 2022. The Author(s).)

Background: Pancreatitis is the most common complication following endoscopic retrograde cholangiopancreatography (ERCP). In patients receiving NSAID prophylaxis, we aimed to assess whether periprocedural intensive hydration (IH) resulted in a lower incidence of PEP when compared to standard hydration (SH)., Material and Methods: Prospective, single-center, double-blinded randomized controlled trial, with inclusion of consecutive patients submitted to inaugural ERCP between January 2015 and December 2018. Patients were randomized on admission, in a 1:1 ratio, to either SH-Ringer's Lactate (RL) at a rate of 1.5 mL/kg/h during and for 8 h following the procedure, or IH-RL at a rate of 3 mL/kg/h during and for 8 h following the procedure, with an additional bolus of 20 mL/kg at the end of the procedure. PEP incidence and severity were assessed according to the Atlanta Guidelines., Results: A total of 155 patients were randomized (83 to IH, 72 to SH). PEP was observed in 8,4% (n = 13) of the patients, and was significantly less frequent in IH patients when compared to SH (3,6% vs 13,9%, P = 0,021; relative risk 0.233 [95% IC, 0.061-0.881]); five patients in the SH group developed moderate to severe PEP, in contrast to 0 patients in the IH group (6.9% vs 0.0%, P = 0,020)., Conclusions: Intensive hydration significantly decreased the risk of post-ERCP pancreatitis by four-fold. Moreover, no cases of moderate or severe pancreatitis were observed in patients submitted to this intervention. Associated with nonsteroidal anti-inflammatory drugs, intensive hydration could constitute a new standard of care for patients undergoing ERCP., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The RECOURSE trial supported trifluridine/tipiracil as a treatment option in metastatic colorectal cancer (mCRC). Subsequent analysis demonstrated that low tumour burden and indolent disease are good prognosis factors improving progression-free survival (PFS) and overall survival (OS). This study aimed to evaluate the impact of prognosis group in the OS, PFS and safety of trifluridine/tipiracil in patients with mCRC., Methods: Single-centre, retrospective, and observational study of patients with mCRC who started trifluridine/tipiracil between February 2018 and July 2019. Patients were divided into good prognosis characteristics (GPC) [low tumour burden (less than 3 metastasis site) and indolent disease (≥18 months from first metastasis diagnosis)] and poor prognostic characteristics (PPC) group [high tumour burden (3 or more metastasis sites) and/or aggressive disease (<18 months since the first metastasis diagnosis)]., Results: Median age was 67 years (48-82), 67.3% of the patients were male, and 65.3% had stage IV disease at baseline. Overall, median OS was 7.5 months (95%CI:5.7-9.3). Twenty-two patients (44.9%) presented GPC and 29 (59.1%) had PPC. GPC patients had longer median OS [11.4 (95%CI:6.2-16.7)] versus 3.9 months [(95%CI: 3.3-4.6),p < 0.0001] and PFS [4.9 (95%CI:3.0-6.9) versus 2.6 months (95%CI:2.2-2.8),p < 0.0001]. These differences were more pronounced in GPC patients with no liver metastasis. Grade ≥3 adverse events incidence didn't vary between GPC and PPC subgroups., Conclusion: Our study validates the improved trifluridine/tipiracil efficacy in patients with GPC in comparison with PPC while maintaining a well-tolerated safety profile. Indolent disease, low tumour burden and the absence of liver metastasis were shown to be good prognosis factors influencing sustained response to trifluridine/tipiracil., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and study aims  Polyethylene glycol (PEG) bowel preparations are effective but associated with high ingestion volume. In this study, 1-L PEG and 2-L PEG preparations were compared in a randomized, colonoscopist-blinded, single-center trial. Patients and methods  Patients were aged > 18 years, required colonoscopy, and provided informed consent. Randomization was 1:1 to 1-L PEG or 2-L PEG, based on hospital identification number (odd or even). Preparations were administered using same-day dosing adjusted for colonoscopy start time. The primary endpoint was successful bowel preparation on the Boston Bowel Preparation Scale (BBPS) (no segment scored < 2). Results  A total of 852 patients were randomized. In the intention-to-treat (ITT) population, significantly more patients had diabetes in the 2-L PEG arm, resulting in the creation of the modified-ITT population (mITT) that excluded diabetic patients to correct the imbalance (1-L PEG, n = 239; 2-L PEG, n = 238). In the mITT, there was no significant difference in successful cleansing between 1-L PEG and 2-L PEG (88.3 % vs. 82.4 %; P  = 0.067). Excellent cleansing (BBPS 7-9; no segment < 2) was significantly improved with 1-L PEG (60.7 % vs. 50.4 %; P  < 0.024), as were mean scores in the right and left colon (right: 2.47 vs. 2.30; P  < 0.008; left: 2.55 vs. 2.39; P  = 0.008). Adverse events were mild to moderate in intensity and none resulted in discontinuation. Rates of nausea and vomiting were significantly higher with 1-L PEG, but that did not affect successful cleansing. Conclusions  The lower-volume 1-L PEG was associated with higher levels of excellent bowel cleansing and greater mean segmental scores on the BBPS than 2-L PEG., Competing Interests: Competing interests Dr. Rosa has a consulting services agreement with Medtronic., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated whether TTR promotes axon elongation by modulating MT dynamics. We found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in peripheral axons. In addition, they failed to modulate MT dynamics in response to sciatic nerve injury, leading to decreased regenerative capacity. Importantly, restoring acetylated α-tubulin levels of TTR KO dorsal root ganglia (DRG) neurons using an HDAC6 inhibitor is sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results reveal a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation via modulation of the acetylase ATAT1, and suggest that this activity underlies TTR neuritogenic function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eira, Magalhães, Macedo, Pero, Misgeld, Sousa, Bartolini and Liz.)

Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockade of A2A receptors (A2AR) controls the tangential migration of somatostatin+ interneurons. Here we found that A2AR control radial migration of cortical projection neurons. In A2AR-knockout (KO) mouse embryos or naïve mouse embryos exposed to an A2AR antagonist, we observed an accumulation of early-born migrating neurons in the lower intermediate zone at late embryogenesis. In utero knockdown of A2AR also caused an accumulation of neurons at the lower intermediate zone before birth. This entails the presently identified ability of A2AR to promote multipolar-bipolar transition and axon formation, critical for the transition of migrating neurons from the intermediate zone to the cortical plate. This effect seems to require extracellular ATP-derived adenosine since a similar accumulation of neurons at the lower intermediate zone was observed in mice lacking ecto-5'-nucleotidase (CD73-KO). These findings frame adenosine as a fine-tune regulator of the wiring of cortical inhibitory and excitatory networks., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Epithelioid trophoblastic tumour (ETT) is a very rare variant of gestational trophoblastic disease, which arises in reproductive-age women with a prior gestational history. Because of its rarity, its biological behaviour, imaging characteristics and therapeutic schedule have not yet been fully established. Here we describe a rare case of metastatic ETT in a premenopausal woman. A 40-year-old, gravida 3, para 2, Portuguese woman was referred to the dermatology department for multiple skin nodules on the scalp measuring between 1 and 6 cm. A skin biopsy was suggestive of metastatic lesions of low differentiated carcinoma in favour of squamous cell carcinoma. Staging cervical-thoracic-abdominal and pelvic CT showed multiple lesions compatible with metastasis (ganglia, lung and kidneys). Since a CT scan was unable to identify the primary tumour, it was decided to perform a PET-CT scan and to take a biopsy of a vulvar nodule which had been clinically identified as ETT. The patient began the EMA-CO protocol and completed two cycles but with clinical worsening and radiological progression. Although several different chemotherapy regimens are used to treat gestational trophoblastic disease, the optimal treatment is not known given the rarity of this disease and the lack of controlled trials., Learning Points: Trophoblastic disease is a rare entity with several presentations at diagnosis.Presentation with dermatological changes may need differential diagnosis to distinguish it from other types of dermatological disease.Quick diagnosis and referral to an appropriate centre are needed., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2021.)

Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The term phyllodes tumours, which account for less than 1% of breast neoplasms, describes a spectrum of heterogenous tumours with different clinical behaviours. Less than 30% present as metastatic disease. Complete surgical resection is the standard of care so that recurrence rates are reduced. The role of adjuvant chemotherapy or radiation therapy is controversial. Patients with metastatic disease have a median overall survival of around 30 months., Case Description: The authors present the case of a 57-year-old woman with an exuberant left malignant phyllodes tumour with bilateral involvement, as well as lung and axillar metastasis. The patient underwent haemostatic radiation therapy and started palliative chemotherapy with doxorubicin, achieving partial response with significant improvement in quality of life. A posterior simple mastectomy revealed a small residual tumour., Discussion: Metastatic malignant phyllodes tumours are rare, so therapeutic strategies rely on small retrospective studies and guidelines for soft tissue sarcoma. Palliative chemotherapy protocols include anthracycline-based regimens, either as monotherapy with doxorubicin or doxorubicin together with ifosfamide. With few treatment options, management of these patients must rely on a continuum of care., Learning Points: Phyllodes tumours are a rare type of breast neoplasm.The differential diagnosis of breast cancer should include phyllodes tumours.Accurate and rapid diagnosis is required., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2021.)

Background: Early diagnosing bacterial infection in cirrhotic patients is critical but challenging. Neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and is an emerging biomarker that replicates cirrhosis' imbalanced immune response., Aim: Assess whether NLR levels associate with higher risk of infection in patients admitted with first cirrhosis decompensation., Methods: Retrospective, unicenter study, including patients with cirrhosis, admitted to the hospital at first decompensation. NLR was calculated at admission. Applying logistic regression models and testing for discriminative power, we correlated NLR with the outcome infection., Results: We included 139 patients. Forty-four infections to report (31.7%), 18 (12.9%) community infections and 26 (18.7%) hospital-acquired infections.Higher NLR values at admission were associated with increased infection risk in univariable and multivariable models - for each unit increase of NLR, infection odds increased 1.29 times (95%CI = 1.09-1.53; p = 0.003), after adjusting for covariates. We performed a classification tree based only on NLR to evaluate the risk of infection. A high-risk group (proportion of patients with infection = 87%) was identified, corresponding to NLR>14; patients with NLR <3.6 presented lower infection risk (17%).Regarding hospital-acquired infection, we were not able to discriminate groups of patients based on classification trees., Conclusion: NLR is a straightforward approach to attest the individual infection risk on cirrhotic patients. We report NLR cutoffs 3.6 and 14 as optimal for overall infection diagnosing, mainly due to community infection.

Introduction: Increasing evidence suggests an association between metabolic-associated fatty liver disease (MAFLD) and CKD. Timely prediction of early kidney dysfunction (EKD) is thus essential in this population although a screening method is not stablished. We aimed to evaluate the role of transient elastography (TE) in predicting EKD in patients with MAFLD., Materials and Methods: A prospective cohort study that included patients with MAFLD scheduled for evaluation was performed between May 2019 and January 2020. Demographic, clinical, and laboratory data and TE parameters were prospectively obtained. EKD was defined as microalbuminuria (urinary albumin-to-Cr ratio 30-300 mg/g) and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. Significant liver fibrosis was defined as liver stiffness measurement (LSM) ≥8.2 kPa., Results: Of the included 45 patients with MALFD, 53.3% were of female gender with mean age of 53.5 ± 10.9 years. EKD was found in 17.8% of patients. MAFLD patients with EKD were significantly more obese (BMI ≥30) (75.0 vs. 32.4%, p = 0.045) and had significantly higher LSM (8.5 ± 4.1 vs. 5.8 ± 2.2 kPa, p = 0.01). After adjustment of potential confounders for EKD, the presence of liver fibrosis remained a significant predictor of EKD, being associated with a 14.3-fold increased risk of EKD (p = 0.04). The optimal cutoff value of LSM to predict EKD was 6.1 kPa (sensitivity: 85.7%; specificity: 67.6%)., Conclusion: Significant liver fibrosis is associated with a significant increased risk of EKD in patients with MAFLD, regardless of other comorbidities. Higher levels of LSM, particularly >6.1 kPa, alert for timely identification of EKD and associated comorbidities, as well as their control, in order to prevent the development of CKD in the long term., (© 2021 S. Karger AG, Basel.)

Several plant species display a temporal separation of the male and female flower organ development to enhance outbreeding; however, little is known regarding the genetic mechanisms controlling this temporal separation. Quercus suber is a monoecious oak tree with accentuated protandry: in late winter, unisexual male flowers emerge adjacent to the swollen buds, whereas unisexual female flowers emerge in the axils of newly formed leaves formed during spring (4-8 weeks after male flowering). Here, a phylogenetic profiling has led to the identification of cork oak homologs of key floral regulatory genes. The role of these cork oak homologs during flower development was identified with functional studies in Arabidopsis thaliana. The expression profile throughout the year of flower regulators (inducers and repressors), in leaves and buds, suggests that the development of male and female flowers may be preceded by separated induction events. Female flowers are most likely induced during the vegetative flush occurring in spring, whereas male flowers may be induced in early summer. Male flowers stay enclosed within the pre-dormant buds, but complete their development before the vegetative flush of the following year, displaying a long period of anthesis that spans the dormant period. Our results portray a genetic mechanism that may explain similar reproductive habits in other monoecious tree species., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Osteoarthritis (OA) is a highly heterogenous disease influenced by different molecular, anatomic, and physiologic imbalances. Some of the bottlenecks for enhanced diagnosis and therapeutic assessment are the lack of validated biomarkers and early diagnosis tools. In this narrative review, we analyze the potential of Raman spectroscopy (RS) as a label-free optical tool for the characterization of articular joint tissues and its application as a diagnosis tool for OA., Areas Covered: Raman spectra produce a unique 'molecular fingerprint' providing rotational and vibrational molecular information, allowing the identification and follow-up of molecular changes associated with OA pathological mechanisms. Focusing on multiple joint tissues (cartilage, synovium, bone, tendons, ligaments, and meniscus) and their contribution in disease incidence and progression, this review highlights the current knowledge on the application of RS in the characterization of organic and inorganic molecules present at these tissues and alterations that occur in the onset of OA., Expert Opinion: Vibrational spectroscopy techniques, such as RS, are low cost, rapid and minimally invasive approaches that offer high specificity in the assessment of the molecular composition of complex tissues. Combined with multivariate statistical methods, RS offers great potential for optical biomarkers discovery or disease diagnosis applications, and we hereby discuss clinical translational progresses on the field.

Primary hepatic tuberculosis is a rare clinical entity with non-specific clinical and imaging features that can mimic other liver diseases, representing a diagnostic challenge. We report a case of a 35-year-old man with metabolic syndrome, type 2 diabetes and high alcohol consumption presenting asymptomatic with abnormal liver tests, hepatosplenomegaly and diffuse hepatic steatosis in ultrasound imaging initially suspected to be alcoholic steatohepatitis but later diagnosed as hepatic tuberculosis in the histological specimen. Anti-tuberculosis therapy was started. This clinical case highlights the diagnostic difficulty of hepatic tuberculosis and the importance of not overlooking liver biopsy and to consider it in the differential diagnosis in patients with obvious hepatic injury factors but with atypical clinical presentation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Lipidomics and proteomics have undergone a tremendous revolution, and the knowledge about drugs' mechanism of action in biological membranes has been deepened. Methods to study the interactions of drugs with biological membranes have opened new perspectives to rational drug design, based not only in the pharmacological target of the drugs but also on the interaction with biological membranes. These methods expand our ability to acquire the ADME-Tox profile of drugs, simplifying the complexity of biological membranes. Particularly, antibiotic resistance is considered one of the greatest threats to human health, being the prospects for replacing current antimicrobial drugs extremely scarce. With the decline of the discovery and the emergence of multidrug resistant pathogens to the existing arsenal, the objective in the development of new drugs to combat the resistance to antibiotics has been replaced by the modification of existing antibiotics. Therefore, drug-membrane interaction studies using membrane models of the eukaryotic and prokaryotic cell membranes, associated with a broad of complementary methods, may contribute to a deep picture concerning the effect of antibiotics upon their intake until their pharmacological target. This critical review will discuss the relevance of a range of different methods to study the interaction of antibiotic drugs using liposomes as biological membranes models. The advantages and the limitations of these methods will be discussed and future perspectives in this field will be proposed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Recent studies suggest an increased prevalence of hepatic steatosis (HS) in patients with inflammatory bowel disease (IBD). Features such as chronic inflammation, previous surgeries, drug-induced hepatotoxicity, malnutrition, and intestinal dysbiosis seem to be involved in its pathogenesis., Aims: The aim of this study was to assess the frequency of HS in patients with IBD quantified by controlled attenuation parameter (CAP) and by clinical-analytical scores: Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI). The secondary aim was to investigate risk factors associated with HS in patients with IBD., Patients and Methods: A cross-sectional study was carried out including consecutive outpatients observed in our department between January and March 2017. HS was defined as HSI of at least 36 or FLI of at least 60 or CAP of greater than 248., Results: A total of 161 patients were included, with a mean age of 40.6±12.8 years. There were 86 (53.4%) female patients. Overall, 62.7% had Crohn's disease and 37.1% had ulcerative colitis. Moreover, 73 (45.3%) patients had CAP greater than 248, 27 (16.8%) had FLI greater than 60, and 46 (28.6%) had HSI greater than 36.We found that patients with CAP of greater than 248 were more frequently obese (28.8 vs. 0.0% P<0.001), male (57.5 vs. 37.5% P=0.011), and presented more frequently with metabolic syndrome (23.9 vs. 4.5% P <0.001). With regard to IBD factors, patients with HS had a higher frequency of previous surgeries (31.5 vs. 12.5% P=0.003). In multivariate analysis, only male sex [odds ratio: 5.7 (95% confidence interval: 2.0-15.9); P=0.001] and previous surgeries [odds ratio: 5.9 (95% confidence interval: 1.5-22.9); P=0.011] were independent risk factors of HS., Conclusion: In our cohort, the frequency of HS varied between 16.8 and 45.3% defined by noninvasive methods. We found that male sex and previous history of surgery were the independent risk factors of HS when quantified by transient elastography.

Introduction: Pulmonary thromboembolism and deep venous thrombosis occur in pediatric age, with unknown incidence, morbidity and mortality. Our aim is to review the epidemiology, clinical presentation, complementary diagnostic tests and prognosis of patients with pulmonary thromboembolism and deep venous thrombosis., Material and Methods: Retrospective, descriptive and analytical study of pediatric patients admitted to a Level II hospital for pulmonary thromboembolism and deep venous thrombosis, between 2000 and 2014. Demographic characteristics, clinical history, comorbidities and risk factors were studied., Results: Eleven patients (n = 7 pulmonary thromboembolism, n = 5 deep venous thrombosis, n = 1 both), 64% females and with 16 years old average, were admitted. All patients with pulmonary thromboembolism presented symptoms of chest pain and/or dyspnea, 25% syncope/palpitations and 25% fever. All patients with deep venous thrombosis reported localized pain at the site of obstruction, 83% edema/cyanosis of the affected limb and 17% fever. The study of positive thrombophilia was the most frequent risk factor in both entities. The mean value of D-dimers was 3252 ug/dL and 2660 ug/dL in pulmonary thromboembolism and deep venous thrombosis, respectively. All patients started anticoagulation, three required intensive care, two had sequelae and one died., Discussion: All patients had at least one risk factor, and hereditary hypercoagulability was most commonly established., Conclusions: The increased incidence in the pediatric population described in some studies can be attributed to an increased awareness of this pathology, medical advances and increasing survival of chronic diseases. There is a lack of evidence-based recommendations identifying patients at risk of thrombosis so that decisions can be made carefully, balancing the risk and benefit in each case.

In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC 50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC 50 values in the low μM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Aim: To compare the findings and completion rate of PillCam® SB2 and SB3., Methods: This was a retrospective single-center study that included 357 consecutive small bowel capsule endoscopies (SBCE), 173 SB2 and 184 SB3. The data collected included age, gender, capsule type (PillCam® SB2 or SB3), quality of bowel preparation, completion of the examination, gastric and small bowel transit time, small bowel findings, findings in segments other than the small bowel and the detection of specific anatomical markers, such as the Z line and papilla., Results: The mean age of the patients was 48 years and 66.9% were female. The two main indications were suspicion/staging of inflammatory bowel disease (IBD) and obscure gastrointestinal bleeding (OGIB) (43.7% and 40.3%, respectively). Endoscopic findings were reported in 76.2% of examinations and 53.5% were relevant findings. No significant differences were found between SB2 and SB3 with regard to completion rate (93.6% vs 96.2%, p = 0.27), overall endoscopic findings (73.4% vs 78.8%, p = 0.23), relevant findings (54.3% vs 52.7%, p = 0.76), first tertile findings (43.9% vs 48.9%, p = 0.35), extra-SB findings (23.7% vs 17.3%, p = 0.14), Z line and papilla detection rate (35.9% vs 35.7%, p = 0.97 and 27.1% vs 32.6%, p = 0.32, respectively). With regard to the patient subgroups with suspicion/staging of IBD, significant differences were found in relation to the detection of villous edema and the 3rd tertile findings, thus favoring SB3 (26.3% vs 43.8%, p = 0.02 and 47.4% vs 66.3%, p = 0.02, respectively). Mucosal atrophy was significantly more frequently diagnosed with the PillCam® SB3 in patients with anemia/OGIB (0% vs 8%, p = 0.03)., Conclusions: Overall, PillCam® SB3 did not improve the diagnostic yield compared to SB2, although it improved the detection of villous atrophy and segmental edema.

Upper gastrointestinal bleeding (UGIB) remains a significant cause of hospital admission. In order to stratify patients according to the risk of the complications, such as rebleeding or death, and to predict the need of clinical intervention, several risk scores have been proposed and their use consistently recommended by international guidelines. The use of risk scoring systems in early assessment of patients suffering from UGIB may be useful to distinguish high-risks patients, who may need clinical intervention and hospitalization, from low risk patients with a lower chance of developing complications, in which management as outpatients can be considered. Although several scores have been published and validated for predicting different outcomes, the most frequently cited ones are the Rockall score and the Glasgow Blatchford score (GBS). While Rockall score, which incorporates clinical and endoscopic variables, has been validated to predict mortality, the GBS, which is based on clinical and laboratorial parameters, has been studied to predict the need of clinical intervention. Despite the advantages previously reported, their use in clinical decisions is still limited. This review describes the different risk scores used in the UGIB setting, highlights the most important research, explains why and when their use may be helpful, reflects on the problems that remain unresolved and guides future research with practical impact.

Aim: To evaluate whether virtual chromoendoscopy can improve the delineation of small bowel lesions previously detected by conventional white light small bowel capsule endoscopy (SBCE)., Methods: Retrospective single center study. One hundred lesions selected from forty-nine consecutive conventional white light SBCE (SBCE-WL) examinations were included. Lesions were reviewed at three Flexible Spectral Imaging Color Enhancement (FICE) settings and Blue Filter (BF) by two gastroenterologists with experience in SBCE, blinded to each other's findings, who ranked the quality of delineation as better, equivalent or worse than conventional SBCE-WL. Inter-observer percentage of agreement was determined and analyzed with Fleiss Kappa (κ) coefficient. Lesions selected for the study included angioectasias (n = 39), ulcers/erosions (n = 49) and villous edema/atrophy (n = 12)., Results: Overall, the delineation of lesions was improved in 77% of cases with FICE 1, 74% with FICE 2, 41% with FICE 3 and 39% with the BF, with a percentage of agreement between investigators of 89% (κ = 0.833), 85% (κ = 0.764), 66% (κ = 0.486) and 79% (κ = 0.593), respectively. FICE 1 improved the delineation of 97.4% of angioectasias, 63.3% of ulcers/erosions and 66.7% of villous edema/atrophy with a percentage of agreement of 97.4% (κ = 0.910), 81.6% (κ = 0.714) and 91.7% (κ = 0.815), respectively. FICE 2 improved the delineation of 97.4% of angioectasias, 57.1% of ulcers/erosions and 66.7% of villous edema/atrophy, with a percentage of agreement of 89.7% (κ = 0.802), 79,6% (κ = 0.703) and 91.7% (κ = 0.815), respectively. FICE 3 improved the delineation of 46.2% of angioectasias, 24.5% of ulcers/erosions and none of the cases of villous edema/atrophy, with a percentage of agreement of 53.8% [κ = not available (NA)], 75.5% (κ = NA) and 66.7% (κ = 0.304), respectively. The BF improved the delineation of 15.4% of angioectasias, 61.2% of ulcers/erosions and 25% of villous edema/atrophy, with a percentage of agreement of 76.9% (κ = 0.558), 81.6% (κ = 0.570) and 25.0% (κ = NA), respectively., Conclusion: Virtual chromoendoscopy can improve the delineation of angioectasias, ulcers/erosions and villous edema/atrophy detected by SBCE, with almost perfect interobserver agreement for FICE 1.

Aim: To evaluate whether the use of real time viewer (RTV) and administration of domperidone to patients with delayed gastric passage of the capsule could reduce the rate of incomplete examinations (IE) and improve the diagnostic yield of small bowel capsule endoscopy (SBCE)., Methods: Prospective single center interventional study, from June 2012 to February 2013. Capsule location was systematically checked one hour after ingestion using RTV. If it remained in the stomach, the patient received 10 mg domperidone per os and the location of the capsule was rechecked after 30 min. If the capsule remained in the stomach a second dose of 10 mg of domperidone was administered orally. After another 30 min the position was rechecked and if the capsule remained in the stomach, it was passed into the duodenum by upper gastrointestinal (GI) endoscopy. The rate of IE and diagnostic yield of SBCE were compared with those of examinations performed before the use of RTV or domperidone in our Department (control group, January 2009 - May 2012)., Results: Both groups were similar regarding age, sex, indication, inpatient status and surgical history. The control group included 307 patients, with 48 (15.6%) IE. The RTV group included 82 patients, with 3 (3.7%) IE, P = 0.003. In the control group, average gastric time was significantly longer in patients with IE than in patients with complete examination of the small bowel (77 min vs 26 min, P = 0.003). In the RTV group, the capsule remained in the stomach one hour after ingestion in 14/82 patients (17.0%) vs 48/307 (15.6%) in the control group, P = 0.736. Domperidone did not significantly affect small bowel transit time (260 min vs 297 min, P = 0.229). The capsule detected positive findings in 39% of patients in the control group and 49% in the RTV group (P = 0.081)., Conclusion: The use of RTV and selective administration of domperidone to patients with delayed gastric passage of the capsule significantly reduces incomplete examinations, with no effect on small bowel transit time or diagnostic yield.

Aim: To evaluate small bowel cleansing quality, diagnostic yield and transit time, comparing three cleansing protocols prior to capsule endoscopy., Methods: Sixty patients were prospectively enrolled and randomized to one of the following cleansing protocols: patients in Group A underwent a 24 h liquid diet and overnight fasting; patients in Group B followed protocol A and subsequently were administered 2 L of polyethylene glycol (PEG) the evening before the procedure; patients in Group C followed protocol B and were additionally administered 100 mg of simethicone 30 min prior to capsule ingestion. Small bowel cleansing was independently assessed by two experienced endoscopists and classified as poor, fair, good or excellent according to the proportion of small bowel mucosa under perfect conditions for visualization. When there was no agreement between the two endoscopists, the images were reviewed and discussed until a consensus was reached. The preparation was considered acceptable if > 50% or adequate if > 75% of the mucosa was in perfect cleansing condition. The amount of bubbles was assessed independently and it was considered significant if it prevented a correct interpretation of the images. Positive endoscopic findings, gastric emptying time (GET) and small bowel transit time (SBTT) were recorded for each examination., Results: There was a trend favoring Group B in achieving an acceptable (including fair, good or excellent) level of cleansing (Group A: 65%; Group B: 83.3%; Group C: 68.4%) [P = not significant (NS)] and favoring Group C in attaining an excellent level of cleansing (Group A: 10%; Group B: 16.7%; Group C: 21.1%) (P = NS). The number of patients with an adequate cleansing of the small bowel, corresponding to an excellent or good classification, was 5 (25%) in Group A, 5 (27.8%) in Group B and 4 (21.1%) in Group C (P = 0.892). Conversely, 7 patients (35%) in Group A, 3 patients (16.7%) in Group B and 6 patients (31.6%) in Group C were considered to have poor small bowel cleansing (P = 0.417), with significant fluid or debris such that the examination was unreliable. The proportion of patients with a significant amount of bubbles was 50% in Group A, 27.8% in Group B and 15.8% in Group C (P = 0.065). This was significantly lower in Group C when compared to Group A (P = 0.026). The mean GET was 27.8 min for Group A, 27.2 min for Group B and 40.7 min for Group C (P = 0.381). The mean SBTT was 256.4 min for Group A, 256.1 min for Group B and 258.1 min for Group C (P = 0.998). Regarding to the rate of complete examinations, the capsule reached the cecum in 20 patients (100%) in Group A, 16 patients (88.9%) in Group B and 17 patients (89.5%) in Group C (P = 0.312). A definite diagnosis based on relevant small bowel endoscopic lesions was established in 60% of the patients in Group A (12 patients), 44.4% in Group B (8 patients) and 57.8% in Group C (11 patients) (P = 0.587)., Conclusion: Preparation with 2 L of PEG before small bowel capsule endoscopy (SBCE) may improve small bowel cleansing and the quality of visualization. Simethicone may further reduce intraluminal bubbles. No significant differences were found regarding GET, SBTT and the proportion of complete exploration or diagnostic yield among the three different cleansing protocols.