Local Antimicrobial Resistance Trends in Pediatric Urinary Tract Infection: The Importance of Local Surveillance of a Global Problem.

Introduction Urinary tract infections (UTIs) are one of the most common pediatric bacterial infections and consequently a major reason for antibiotic treatment. Despite being a global problem, antimicrobial resistance is often geographically heterogeneous. Thus, it is fundamental to know local epidemiology and practice frequent surveillance of each hospital's antibiograms. The aims of this study are to determine the local antimicrobial resistance profile in pediatric UTIs, to understand its evolution over 14 years, and finally, to infer if the currently instituted antibiotic empirical therapy remains effective. Materials and methods A retrospective observational study was performed through the analysis of urine cultures and respective antibiograms of children diagnosed with UTI from 2017 to 2019 in Centro Hospitalar Universitário do Algarve (Faro's unit, Portugal), followed by a comparison of the obtained data with the results of a similar study performed between 2003 and 2005. Results A total of 784 urine cultures were selected. Escherichia coli was the most frequent microorganism (n = 561; 71.56%), followed by Proteus mirabilis (n = 117; 14.92%) and Klebsiella pneumoniae (n = 40; 5.10%). The most commonly prescribed antibiotic was cefuroxime axetil (66.28%). Escherichia coli had an increase in resistance to amoxicillin-clavulanate of 6.16% to 34.76% and cefuroxime axetil of 0.73% to 4.46%. Proteus mirabilis had an increase in resistance to amoxicillin-clavulanate of 1.64% to 11.11%. Klebsiella pneumoniae had an increase in resistance to cefuroxime axetil (0%-27.50%) and nitrofurantoin (0%-47.50%). The three microorganisms showed a decrease in trimethoprim-sulfamethoxazole resistance profiles, as well as low resistance profiles to fosfomycin. In fifty cases in which antibiotic empirical therapy was instituted, the isolated microorganism revealed in vitro resistance; 37 of these cases had a good evolution, maintaining the antibiotic empirical therapy. Discussion Local surveillance of antimicrobial resistance allows monitoring of the resistance trends and adequacy of empirical antibiotic therapy. This study's local resistance profile was distinct from other regions of the country and the world. Continuous local surveillance also potentiates the dissemination of the results to the concerned healthcare providers and the initiation of timely responsive measures, containing the increase in antimicrobial resistance. As Escherichia coli was the commonest isolated microorganism, its antimicrobial profile should dictate antibiotic empirical therapy. This study supports that in vitro is not equivalent to in vivo resistance. Conclusion There was a significant increase in antimicrobial resistance profiles, especially to amoxicillin-clavulanate. Cefuroxime axetil remains the recommended antibiotic for empirical therapy in this hospital, although fosfomycin should be considered as an alternative in non-complicated cystitis in adolescent females. This study reinforces the importance of continuous local resistance surveillance as a preventive measure against the global increase in antimicrobial resistance.

Microfluidic Paper-Based Device Incorporated with Silica Nanoparticles for Iodide Quantification in Marine Source Dietary Supplements.

Iodine is an essential micronutrient for humans due to its fundamental role in the biosynthesis of thyroid hormones. As a key parameter to assess health conditions, iodine intake needs to be monitored to ascertain and prevent iodine deficiency. Iodine is available from various food sources (such as seaweed, fish, and seafood, among others) and dietary supplements (multivitamins or mineral supplements). In this work, a microfluidic paper-based analytical device (µPAD) to quantify iodide in seaweed and dietary supplements is described. The developed µPAD is a small microfluidic device that emerges as quite relevant in terms of its analytical capacity. The quantification of iodide is based on the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by hydrogen peroxide in the presence of iodine, which acts as the catalyst to produce the blue form of TMB. Additionally, powder silica was used to intensify and uniformize the colour of the obtained product. Following optimization, the developed µPAD enabled iodide quantification within the range of 10-100 µM, with a detection limit of 3 µM, and was successfully applied to seaweeds and dietary supplements. The device represents a valuable tool for point-of-care analysis, can be used by untrained personnel at home, and is easily disposable, low-cost, and user-friendly.

A Rare Cause of Intellectual Disability.

A seven-year-old female was followed in a developmental clinic from the age of nine months due to delayed psychomotor development. The first physical examination showed a newborn with irritability and a large anterior fontanelle. A transfontanellar ultrasound was performed, revealing mild enlargement of the lateral and third ventricles. Head circumference remained below the third percentile until the age of five months, then rose to the third percentile. Developmental milestones were globally delayed, with expressive language being more severely affected and axial hypotonia with appendicular hypertonia on neurological examination. Subsequent medical observation revealed deep-set eyes, mildly up-slanted palpebral fissures, a high nasal bridge with a broad nasal tip, a thin upper lip, widely spaced teeth, retrognathia, and a slight pectus excavatum. Genetic investigation revealed the diagnosis, with whole-exome sequencing consistent with the genetic diagnosis of autosomal dominant mental retardation type 7 (MRD7). All patients diagnosed with MRD7 have a development delay detected at a young age and, typically, a mild to severe intellectual disability later in life. All individuals present language impairment, especially in verbal expression. Motor development is typically affected by gait disturbances and generalized hypertonia, which are noted early in life. Microcephaly is a prominent feature of this syndrome, present in over 90% of the cases. The most common findings in MRD7 (microcephaly and intellectual disability) have a broad differential diagnosis. Some disorders have multiple findings in common with MRD7, such as Angelman syndrome (AS), MECP2 disorders, or Mowat-Wilson syndrome (MWS). MRD7 is a rare genetic syndrome characterized by developmental delay/intellectual disability, microcephaly, autism spectrum disorder, behavior problems, typical facial features, and seizures. Early intervention is more likely to be effective and potentially change a child's developmental path. Small gains early in life could represent a significant difference in the children's future autonomy.

Supporting Nature-Based Solutions via Nature-Based Thinking across European and Latin American cities.

Nature-Based Solutions concepts and practices are being used worldwide as part of attempts to address societal challenges but have also been criticised for not dealing with deeper transformations needed to face urgent issues including biodiversity loss, climate change and inclusion. In this paper, we explore how an inclusive, integrated and long-sighted approach, emphasising a more radical integration of nature within cities, might support the transformations needed to endure major contemporary challenges. Addressing important emerging critiques of Nature-Based Solutions, we consider the potential of a more incisive form of Nature-Based Thinking (NBT) in cities, based on more holistic perspectives. The paper draws on a reflective and iterative research process that engaged both the research and practice communities through a symposium and a series of futures workshops that together explored the potential of NBT to develop future nature-cities relations in Europe and Latin America. The results of the reflective process suggest that notions of nature with people-not for people- new organisational structures, and the intention and capacity to apply long-term perspectives, are needed when planning for NBS interventions aimed at sustainable urban development. This includes developing a cultural-structural change based on new and inclusive understandings of human-nature relations, and novel governance paradigms that allow cross-sectoral coordination and engagement of local stakeholders beyond formal organisational structures.

Enhancing host-pathogen phenotyping dynamics: early detection of tomato bacterial diseases using hyperspectral point measurement and predictive modeling.

Early diagnosis of plant diseases is needed to promote sustainable plant protection strategies. Applied predictive modeling over hyperspectral spectroscopy (HS) data can be an effective, fast, cost-effective approach for improving plant disease diagnosis. This study aimed to investigate the potential of HS point-of-measurement (POM) data for in-situ, non-destructive diagnosis of tomato bacterial speck caused by Pseudomonas syringae pv. tomato (Pst), and bacterial spot, caused by Xanthomonas euvesicatoria (Xeu), on leaves (cv. cherry). Bacterial artificial infection was performed on tomato plants at the same phenological stage. A sensing system composed by a hyperspectral spectrometer, a transmission optical fiber bundle with a slitted probe and a white light source were used for spectral data acquisition, allowing the assessment of 3478 spectral points. An applied predictive classification model was developed, consisting of a normalizing pre-processing strategy allied with a Linear Discriminant Analysis (LDA) for reducing data dimensionality and a supervised machine learning algorithm (Support Vector Machine - SVM) for the classification task. The predicted model achieved classification accuracies of 100% and 74% for Pst and Xeu test set assessments, respectively, before symptom appearance. Model predictions were coherent with host-pathogen interactions mentioned in the literature (e.g., changes in photosynthetic pigment levels, production of bacterial-specific molecules, and activation of plants' defense mechanisms). Furthermore, these results were coherent with visual phenotyping inspection and PCR results. The reported outcomes support the application of spectral point measurements acquired in-vivo for plant disease diagnosis, aiming for more precise and eco-friendly phytosanitary approaches.

The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes.

Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

Kiwi Plant Canker Diagnosis Using Hyperspectral Signal Processing and Machine Learning: Detecting Symptoms Caused by Pseudomonas syringae pv. actinidiae.

Pseudomonas syringae pv. actinidiae (Psa) has been responsible for numerous epidemics of bacterial canker of kiwi (BCK), resulting in high losses in kiwi production worldwide. Current diagnostic approaches for this disease usually depend on visible signs of the infection (disease symptoms) to be present. Since these symptoms frequently manifest themselves in the middle to late stages of the infection process, the effectiveness of phytosanitary measures can be compromised. Hyperspectral spectroscopy has the potential to be an effective, non-invasive, rapid, cost-effective, high-throughput approach for improving BCK diagnostics. This study aimed to investigate the potential of hyperspectral UV-VIS reflectance for in-situ, non-destructive discrimination of bacterial canker on kiwi leaves. Spectral reflectance (325-1075 nm) of twenty plants were obtained with a handheld spectroradiometer in two commercial kiwi orchards located in Portugal, for 15 weeks, totaling 504 spectral measurements. Several modeling approaches based on continuous hyperspectral data or specific wavelengths, chosen by different feature selection algorithms, were tested to discriminate BCK on leaves. Spectral separability of asymptomatic and symptomatic leaves was observed in all multi-variate and machine learning models, including the FDA, GLM, PLS, and SVM methods. The combination of a stepwise forward variable selection approach using a support vector machine algorithm with a radial kernel and class weights was selected as the final model. Its overall accuracy was 85%, with a 0.70 kappa score and 0.84 F-measure. These results were coherent with leaves classified as asymptomatic or symptomatic by visual inspection. Overall, the findings herein reported support the implementation of spectral point measurements acquired in situ for crop disease diagnosis.

Experimental and numerical investigation of the effect of ultrasound on the growth kinetics of zeolite A.

Ultrasound is a promising technology for the improvement of zeolite production, due to its beneficial effects on mass transfer and nucleation. However, a broad understanding of the sonication parameters that influence the growth of zeolites most is still lacking. In the present work, zeolite A was synthesized and the kinetic model of Gualtieri was used to obtain information about the crystallization parameters. The effect of the sonication power and duration on the relative crystallinity and particle size distribution were investigated using a Langevin-type transducer operating at 40 kHz. The experimental data shows that ultrasound has a significant effect on the nucleation and growth. With that, a reduction of up to 40 % of the initial synthesis time can be achieved. Additionally, a narrower particle size distribution is achieved when ultrasound is used during the zeolite A synthesis.

Stroke and refractory hypoxaemia: complications of pulmonary embolism.

Acute pulmonary embolism is one of the main causes of cardiovascular mortality. Treatment should be guided according to mortality risk stratification, but an individualised and multidisciplinary approach is often required. Concomitant persistent hypoxaemia can be present in cases of intracardiac shunt. In this report, we describe a 46-year-old woman with a history of surgery, presenting with pulmonary embolism with refractory hypoxaemia and simultaneous ischaemic stroke. Fibrinolysis was successfully performed, and the patient made a full recovery. Additional investigations identified a patent foramen ovale, which was later closed. She had no recurrent thrombotic events.

Cardiac Tamponade in Adrenoleukodystrophy with Addison's Disease.

Cardiac tamponade is a life-threatening medical emergency and can arise in many clinical situations. We present the case of a 59-year-old man with adrenoleukodystrophy and Addison's disease who was admitted to the emergency department with severe abdominal pain that turned out to be cardiac tamponade of unknown aetiology. An association between cardiac tamponade and Addison's disease has been reported in the literature, so this aetiology should be considered in the differential diagnosis for patients presenting with unexplained cardiac tamponade. LEARNING POINTS: Cardiac tamponade can be associated with Addison's disease in rare cases.A high level of suspicion is essential, as it can mimic many medical conditions.Emergent pericardiocentesis is the required treatment.

Myasthenia gravis and prostatic neoplasia: a rare association.

An 88-year-old male patient presented with left ptosis, diplopia, muscle weakness of the lower limbs, dysphagia for solids, dysphonia and constipation. On investigation, he was found to have myasthenia gravis (MG). Further evaluation for the possible cause of MG, with CT scan, revealed that the patient had concomitant prostatic cancer. The patient was given steroids and pyridostigmine, with consequent resolution of his neurological symptoms. This is a rare case of MG associated with prostatic cancer.

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theß2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

Effects of ultrasonic irradiation on crystallization kinetics, morphological and structural properties of zeolite FAU.

In this work, NaX zeolite was synthesized and the effect of ultrasound irradiation on reaction kinetics, morphological and structural properties was investigated. Ultrasound was applied, by using a plate transducer (91.8 kHz), for the first time during the crystallization of zeolite NaX, at high temperature, varying the irradiation moment and its duration. Furthermore, ultrasound was applied after the crystallization by a horn-type transducer (20-24 kHz) at low temperature. The effects of irradiated volume (100-300 mL), sonication time (2-10 min) and ultrasound power (10-200 W) were studied with a power intensity up to 100 W/cm2. It was found that the application of ultrasound during the first hour of crystallization resulted in 20% reduction of reaction time compared to a standard crystallization. Ultrasound can also reduce the agglomeration degree of the final powder by combining high power and long sonication time. After 5 min sonication time at 0.3 W/mL, the tapped density of the powder was increased by 10%, from 0.37 to 0.41 g/mL. Finally, by scanning electron microscopy (SEM) it was demonstrated that ultrasound can disrupt the agglomerates without affecting the morphology of individual crystals.

NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons.

Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPY-deficient mice fail to rapidly increase food intake during the first hour of either chemo- or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice. Acutely stimulating AgRP neurons fails to induce systemic insulin resistance in NPY-deficient mice, while increased locomotor activity upon AgRP neuron stimulation in the absence of food remains unaffected in these animals. Selective re-expression of NPY in AgRP neurons attenuates the reduced feeding response and reverses the protection from insulin resistance upon optogenetic activation of AgRP neurons in NPY-deficient mice. Collectively, these experiments reveal a pivotal role of NPY-dependent signaling in mediating the rapid feeding inducing effect and the acute glucose regulatory function governed by AgRP neurons.

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit.

Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin (Sst)-neurons that express the melanocortin receptor Mc4r, elevated growth hormone (GH) expression in the pituitary, and enhanced somatic growth. Mc4r expression and αMSH responsiveness are conserved in Sst-expressing hypothalamic neurons of mice. Thus, acquired leptin resistance and attenuation of pomca transcription in response to excessive caloric intake may represent an ancient mechanism to promote somatic growth when food resources are plentiful.

The Sense of Smell Impacts Metabolic Health and Obesity.

Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of ß-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.

Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance.

Low-grade inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Interleukin-6 (IL-6) is a crucial regulator of T cells and is increased in obesity. Here we report that classical IL-6 signalling in T cells promotes inflammation and insulin resistance during the first 8 weeks on a high-fat diet (HFD), but becomes dispensable at later stages (after 16 weeks). Mice with T cell-specific deficiency of IL-6 receptor-α (IL-6RαT-KO) exposed to a HFD display improved glucose tolerance, insulin sensitivity and inflammation in liver and EWAT after 8 weeks. However, after 16 weeks, insulin resistance in IL-6RαT-KO epididymal white adipose tissue (EWAT) is comparable to that of controls, whereas the inflammatory profile is significantly worse. This coincided with a shift from classical T cell IL-6 signalling at 8 weeks, to enhanced IL-6 trans-signalling at 16 weeks. Collectively, our studies reveal that IL-6 action in T cells through classical IL-6 signalling promotes inflammation and insulin resistance early during obesity development, which can be compensated for by enhanced IL-6 trans-signalling at later stages.

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.

Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.