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The attachment of porous media to a blunt trailing edge (TE) can significantly suppress vortex shedding processes and the related tonal noise, yet the near-wall and internal flow fields of porous media are difficult to analyze experimentally and rely on numerical simulations to elucidate the internal flow features. A structured porous trailing edge (SPTE) has been recently designed that follows a methodology of a structured porous coated cylinder. The SPTE acoustic response was compared against randomized porous media with 10 and 30 pores/in. in an anechoic wind tunnel over a range of flow velocities. Acoustic beamforming revealed that the dominant acoustic sources were at the end of the solid plate, even when a porous TE was attached. A region of integration was used to extract acoustic spectra without additional noise sources, revealing that the SPTE possesses superior noise reduction capability. Dipolar directivity patterns were observed at the vortex shedding frequency for each TE, and the coherence between microphones revealed the complex acoustic propagation of the high-frequency content. A wavelet analysis revealed how the SPTE breaks periodic vortex shedding cycles into smaller cycles over a wider frequency range, leading to an overall noise reduction relative to the other TEs., (© 2024 Acoustical Society of America.)

Background: Paracoccidioidomycosis (PCM) may involve the hepatic pedicle and peripancreatic lymph nodes, cause damage to the bile duct and manifest, exceptionally, in combination with extrahepatic cholestasis (EHC), making investigation and treatment challenging., Aim: To investigate the management of patients with visceral PCM admitted with EHC., Methods: All patients diagnosed with PCM treated in a public, tertiary teaching hospital between 1982 and 2020 were retrospectively evaluated. Those also identified with EHC were allocated to two groups according to the treatment approach for the purpose of comparing clinical, laboratory, and imaging findings, resources used for etiological diagnosis, treatment results, and prognosis. Statistical analyses were performed using the linear mixed-effects model (random and fixed effects), which was adjusted using the PROC MIXED procedure of the SAS ® 9.0 software, and Fisher's exact test., Results: Of 1645 patients diagnosed with PCM, 40 (2.4%) had EHC. Of these, 20 (50.0%) lived in the rural area and 29 (72.5%) were men, with a mean age of 27.1 years (3-65 years). Jaundice as first symptom and weight loss of at least 10 kg were observed in 16 patients (40.0%), and a mass in the head of the pancreas was observed in 8 (20.0%). The etiological diagnosis was made by tissue collection during surgery in 4 cases (10.0%) and by endoscopic methods in 3 cases (7.5%). Twenty-seven patients (67.5%) received drug treatment alone (Group 1), whereas 13 (32.5%) underwent endoscopic and/or surgical procedures in combination with drug treatment (Group 2). EHC was significantly reduced in both groups (40.7% in Group 1, with a mean time of 3 months; and 38.4% in Group 2, with a mean time of 7.5 months), with no statistically significant difference between them. EHC recurrence rates, associated mainly with treatment nonadherence, were similar in both groups: 37% in Group 1 and 15.4% in Group 2. The mortality rate was 18.5% in Group 1 and 23% in Group 2, with survival estimates of 71.3% and 72.5%, respectively, with no statistically significant difference., Conclusion: Although PCM-related EHC is rare, it needs to be included in the differential diagnosis of malignancies, as timely treatment can prevent hepatic and extrahepatic sequelae., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Understanding the mechanical failure modes of lithium-ion battery [Li-ion batteries (LIBs)] electrodes is exceptionally important for enabling high specific energy and flexible LIB technologies. In this work, the failure modes of lithium cobalt oxide (LCO) cathodes under repeated bending and the role of the polymer binder in improving the mechanical durability of the LCO electrodes for use in flexible LIBs are investigated. Mechanical and electrochemical evaluations of LCO electrodes (areal capacity of ≥2.5 mA h cm -2 ) employing poly(vinylidene fluoride) (PVDF) binder were carried out, followed by extensive optical and electron microscopies. We find that the molecular weight (MW) of the PVDF significantly influenced the surface and bulk microstructure of the LCO electrodes, particularly the distribution of carbon additive and binder, which plays a crucial role in affecting the mechanical and electrochemical properties of the electrodes. Multiple mechanical failure modes (e.g., surface scratches and microcracks) observed in the LCO electrodes subjected to repeated bending originated from the use of low MW PVDF; these failure modes were successfully mitigated by using a high MW PVDF. Remarkably, the optimized flexible LCO electrode incorporating high MW PVDF showed comparable discharge capacity retention during galvanostatic cycling after repeated bending (7000 cycles at 50 mm bending diameter) to electrodes not subjected to the repeated bending. This study highlights the importance of carrying out a comprehensive investigation of the failure mechanisms in flexible electrodes, which identified the pivotal role of the PVDF MW in the electrode microstructure and its effects on the electrode resilience to failure during repeated bending.

The genus Aspergillus harbors human infection-causing pathogens and is involved in the complex one-health challenge of antifungal resistance. Here, a 6-year retrospective study was conducted with Aspergillus spp. isolated from patients with invasive, chronic, and clinically suspected aspergillosis in a tertiary teaching hospital. A total of 64 Aspergillus spp. clinical isolates were investigated regarding molecular identification, biofilm, virulence in Galleria mellonella , antifungal susceptibility, and resistance to amphotericin B and azoles. Aspergillus section Fumigati ( A. fumigatus sensu stricto , 62.5%) and section Flavi ( A. flavus , 20.3%; A. parasiticus , 14%; and A. tamarii , 3.1%) have been identified. Aspergillus section Flavi clinical isolates were more virulent than section Fumigati clinical isolates. Furthermore, scant evidence supports a link between biofilm formation and virulence. The susceptibility of the Aspergillus spp. clinical isolates to itraconazole, posaconazole, voriconazole, and amphotericin B was evaluated. Most Aspergillus spp. clinical isolates (67.2%) had an AMB MIC value equal to or above 2 µg/mL, warning of a higher probability of therapeutic failure in the region under study. In general, the triazoles presented MIC values above the epidemiological cutoff value. The high triazole MIC values of A. fumigatus s.s. clinical isolates were investigated by sequencing the promoter region and cyp51A locus. The Cyp51A amino acid substitutions F46Y, M172V, N248T, N248K, D255E, and E427K were globally detected in 47.5% of A. fumigatus s.s. clinical isolates, and most of them are associated with high triazole MICs. Even so, the findings support voriconazole or itraconazole as the first therapeutic choice for treating Aspergillus infections. This study emphasizes the significance of continued surveillance of Aspergillus spp. infections to help overcome the gap in knowledge of the global fungal burden of infections and antifungal resistance, supporting public health initiatives.

A method for optimizing an automatic selection of values for parameters that feed segmentation algorithms is proposed. Evolutionary optimization techniques in combination with a fitness function based on a mutual information parameter have been used to find the optimal parameter values of region growing, fuzzy c-means and graph cut segmentation algorithms. To validate the method, the segmentation of two transmission electron microscopy tomography reconstructed volumes of a carbon black-reinforced rubber and a polylactic acid and clay nanocomposite is carried out (i) using evolutionary optimization techniques and (ii) manually by experts. The results confirm that the use of evolutionary optimization techniques, such as genetic algorithms, reduces the computational operation cost needed for a total grid search of segmentation parameters, reducing the probability of reaching a false optimum, and improving the segmentation quality. HIGHLIGHTS: A new approach to optimize 3D segmentation algorithms. Methodology to optimize segmentation parameters and improve segmentation quality. Improvement on the results when using region growing, fuzzy c-means and graph cuts algorithms., (© 2023 The Authors. Microscopy Research and Technique published by Wiley Periodicals LLC.)

The efficiency of an electrochemical oxidation/reduction process strongly depends on the working electrode's surface area to volume ratio. By making electrodes flexible and employing different configurations such as roll-to-roll membrane, the surface area to volume ratio can be enhanced, therefore improving the overall efficiency of electrochemical processes. Conductive polymers emerge as a new framework to enable alternative electrochemical water treatment cell configurations. Self-standing polypyrrole flexible electrodes were synthesized by electropolymerization and evaluated on the treatment of an oxyanion pollutant: nitrite. Mechanical characterization through stress-strain curves and bending tests demonstrated high electrode resilience that sustained over 1000 bending cycles without impacting mechanical integrity or electrocatalytic responses. The electrocatalytic response towards nitrite reduction was assessed under linear scan voltammetry (LSV) and removal performance evaluated under potentiostatic conditions reaching 79% abatement of initial concentrations of nitrite of 15 mg/L [NO 2 - -N]. Self-standing flexible electrodes appear as a novel framework to enable modular compact water treatment unit designs that maximize the electrode area/volume ratio and substitute expensive platinum group metal (PGMs) electrocatalysts., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The hemorrhage risk of unruptured and untreated cerebral arteriovenous malformations (AVMs) has been shown to be higher for female patients than male patients in their child bearing ages. Although it has been neurosurgical practice to advise female patients in their childbearing ages to postpone pregnancy until proven AVM obliteration, there is no literature consensus regarding this potential hemorrhage risk increase., Objective: To accurately quantify the risk increase for AVM hemorrhage during pregnancy., Methods: This study is based on data from previous publications, consisting of known age at the first AVM hemorrhage in 3425 patients. The risk increase during pregnancy could be calculated from the difference in age distribution for the first AVM hemorrhage between male patients and female patients, taking the average pregnancy time per female into account. A comparison was also made with data for all hospital discharges (13 751) in Germany 2008 to 2018 with the diagnosis brain AVM., Results: The average pregnancy and puerperium time was 1.54 years per female in the patient population, which was used to determine the annual AVM hemorrhage risk during pregnancy to be around 9%. The increased risk during pregnancy was further evidenced by analysis of a subgroup of 105 female patients, for which pregnancy status at the time of hemorrhage was known., Conclusion: The quantified annual risk for AVM hemorrhage during pregnancy is about 3 times higher than that of male patients at corresponding age. This provides an important basis for advising female patients with patent AVMs about the increased risk for hemorrhage that a pregnancy would entail., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

In fungal pathogens the cell wall plays an important role in host-pathogen interactions because its molecular components (e.g., polysaccharides and proteins) may trigger immune responses during infection. GPI-anchored proteins represent the main protein class in the fungal cell wall where they can perform several functions, such as cell wall remodeling and adhesion to host tissues. Genomic analysis has identified the complement of GPI-anchored proteins in many fungal pathogens, but the function has remained unknown for most of them. Here, we conducted an RNA expression analysis of GPI-anchored proteins of Paracoccidioides brasiliensis which causes paracoccidioidomycosis (PCM), an important human systemic mycosis endemic in Latin America. The expression of the GPI-anchored proteins was analyzed by quantitative PCR in both the mycelium and yeast forms. qPCR analysis revealed that the transcript levels of 22 of them were increased in hyphae and 10 in yeasts, respectively, while 14 did not show any significant difference in either form. Furthermore, we cloned 46 open reading frames and purified their corresponding GPI-anchored proteins in the budding yeast. Immunoblot and ELISA analysis of four purified GPI-anchored proteins revealed immune reactivity of these proteins against sera obtained from PCM patients. The information obtained in this study provides valuable information about the expression of many GPI-anchored proteins of unknown function. In addition, based on our immune analysis, some GPI-anchored proteins are expressed during infection and therefore, they might serve as good candidates for the development of new diagnostic methods., 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 © 2023 Gonçales, Portis, dos Reis, Basso Júnior, Martinez, Zhu, Pereira, Soares and Coelho.)

Poly(D,L-lactic- co -glycolic acid) (PLGA) is one of the most commonly used drug carriers in nanomedicines because of its biodegradability, biocompatibility and low toxicity. However, the physico-chemical characterization and study of drug release are often lacking the investigation of the glass transition temperature ( T g ), which is an excellent indicator of drug release behavior. In addition, the residual surfactant used during the synthesis of nanoparticles will change the glass transition temperature. We thus prepared PLGA nanoparticles with polymeric (poly(vinyl alcohol) (PVA)) and ionic (didodecyldimethylammonium bromide (DMAB)) surfactant to investigate their influence on the glass transition temperature. Determination of T g in dry and wet conditions were carried out. The use of concentrated surfactant during synthesis resulted in a larger amount of residual surfactant in the resulting particles. Increasing residual PVA content resulted in an increase in particle T g for all but the most concentrated PVA concentrations, while increasing residual DMAB content resulted in no significant change in particle T g . With the presence of residual surfactant, the T g of particle and bulk samples measured in wet conditions is much lower than that in dry conditions, except for bulk PLGA containing the ionic surfactant, which may be related to the plasticizing effect of the DMAB molecules. Notably, the T g of both particles in wet conditions is approaching physiological temperatures where subtle changes in T g could have dramatic effects on drug release properties. In conclusion, the selection of surfactant and the remaining amount of surfactant are crucial parameters to utilize in designing the physico-chemical properties of PLGA particles.

Artificial intelligence, particularly the growth of neural network research and development, has become an invaluable tool for data analysis, offering unrivalled solutions for image generation, natural language processing, and personalised suggestions. In the meantime, biomedicine has been presented as one of the pressing challenges of the 21st century. The inversion of the age pyramid, the increase in longevity, and the negative environment due to pollution and bad habits of the population have led to a necessity of research in the methodologies that can help to mitigate and fight against these changes. The combination of both fields has already achieved remarkable results in drug discovery, cancer prediction or gene activation. However, challenges such as data labelling, architecture improvements, interpretability of the models and translational implementation of the proposals still remain. In haematology, conventional protocols follow a stepwise approach that includes several tests and doctor-patient interactions to make a diagnosis. This procedure results in significant costs and workload for hospitals. In this paper, we present an artificial intelligence model based on neural networks to support practitioners in the identification of different haematological diseases using only rutinary and inexpensive blood count tests. In particular, we present both binary and multiclass classification of haematological diseases using a specialised neural network architecture where data is studied and combined along it, taking into account the clinical knowledge of the problem, obtaining results up to 96% accuracy for the binary classification experiment. Furthermore, we compare this method against traditional machine learning algorithms such as gradient boosting decision trees and transformers for tabular data. The use of these machine learning techniques could reduce the cost and decision time and improve the quality of life for both specialists and patients while producing more precise diagnoses., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2023 Published by Elsevier Ltd.)

Light chain amyloidosis is the most common form of systemic amyloidosis. This disease is caused by the formation and deposition of amyloid fibers made from immunoglobulin light chains. Environmental conditions such as pH and temperature can affect protein structure and induce the development of these fibers. Several studies have shed light on the native state, stability, dynamics, and final amyloid state of these proteins; however, the initiation process and the fibril formation pathway remain poorly understood structurally and kinetically. To study this, we analyzed the unfolding and aggregation process of the 6aJL2 protein under acidic conditions, with temperature changes, and upon mutation, using biophysical and computational techniques. Our results suggest that the differences in amyloidogenicity displayed by 6aJL2 under these conditions are caused by traversing different aggregation pathways, including unfolded intermediates and the formation of oligomers.

β 2 -microglobulin (β 2 m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of β 2 m result in diseases with distinct pathologies. β 2 m-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst β 2 m-V27M is associated with renal failure, with amyloid deposits forming predominantly in the tongue. Here we use cryoEM to determine the structures of fibrils formed from these variants under identical conditions in vitro. We show that each fibril sample is polymorphic, with diversity arising from a 'lego-like' assembly of a common amyloid building block. These results suggest a 'many sequences, one amyloid fold' paradigm in contrast with the recently reported 'one sequence, many amyloid folds' behaviour of intrinsically disordered proteins such as tau and Aβ., (© 2023. The Author(s).)

The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions. In the neocortex, sensory responses are affected by motor activity, however, it is not known whether such sensorimotor interactions occur in the striatum and how they are shaped by dopamine. To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, their responses to whisker deflection during ongoing whisking were attenuated. Dopamine depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, dopamine depletion impaired the discrimination between ipsilateral and contralateral sensory stimulation in both direct and indirect pathway MSNs. Our results show that whisking affects sensory responses in DLS and that striatal representation of both processes is dopamine- and cell type-dependent., (© 2023. The Author(s).)

The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range of human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is increasing sharply. However, the discovery of therapeutic agents has been immensely challenging largely because of (i) the diverse number of aggregation pathways and the multi-conformational and transient nature of the related proteins or peptides and (ii) the under-development of experimental pipelines for the identification of disease-modifying molecules and their mode-of-action. Here, we describe current approaches used in the search for small-molecule modulators able to control or arrest amyloid formation commencing from IDPs and review recently reported accelerators and inhibitors of amyloid formation for this class of proteins. We compare their targets, mode-of-action and effects on amyloid-associated cytotoxicity. Recent successes in the control of IDP-associated amyloid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic precursors of amyloid assembly., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Introduction: Robotic-assisted surgery is gaining popularity because of reported improvement in aesthetic outcomes while reducing the occurrence of complications compared with conventional surgical methods. Deep inferior epigastric perforator (DIEP) flap harvesting has a long track record as a viable procedure for autologous reconstruction of the breast. In this literature review, we describe the feasibility of using the robotic platform in DIEP flap harvest., Methods: The Preferred Reporting Items for Systemic Reviews and Meta-Analysis methodology was to guide the literature review. PubMed and Scopus databases were searched from inception to June 6, 2022. The Medical Subject Heading terms and keywords used to conduct this search are as described: "Robotic AND deep inferior epigastric perforator AND Breast reconstruction.", Results: Seven publications, detailing a total of 56 robotic-assisted DIEP flap harvest procedures, were selected for review. Four publications used the transabdominal preperitoneal approach, whereas 2 exclusively used a totally extraperitoneal approach, and 1 compared the 2 approaches. The measured outcomes included technical feasibility of flap harvest in cadavers, viable flap harvest in live patients, harvest time and pedicle dissection time, pedicle length, fascial incision length, donor site pain, need for postoperative narcotic, donor site morbidity, and hernia formation. Overall, the reviewed articles demonstrated successful DIEP flap harvesting without the need for conversion to the conventional open procedure. Postoperative complications were minimal. Robotic DIEP flap harvest was shown to be safe and there were no reports of donor-site morbidity in the studies reviewed. The main advantages of the robotic approach include decreased postoperative pain and length of hospital stay, along with improved aesthetic outcomes. The main disadvantages are increased operative time and cost., Conclusions: Although at its current iteration, the robotic-assisted DIEP flap is feasible, it may not be practical in all settings. Furthermore, the true benefit of the robotic platform is yet to be determined, as more long-term studies are necessary., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Self-association of WT β 2- microglobulin (WT-β 2 m) into amyloid fibrils is associated with the disorder dialysis related amyloidosis. In the familial variant D76N-β 2 m, the single amino acid substitution enhances the aggregation propensity of the protein dramatically and gives rise to a disorder that is independent of renal dysfunction. Numerous biophysical and structural studies on WT- and D76N-β 2 m have been performed in order to better understand the structure and dynamics of the native proteins and their different potentials to aggregate into amyloid. However, the structural properties of transient D76N-β 2 m oligomers and their role(s) in assembly remained uncharted. Here, we have utilized NMR methods, combined with photo-induced crosslinking, to detect, trap, and structurally characterize transient dimers of D76N-β 2 m. We show that the crosslinked D76N-β 2 m dimers have different structures from those previously characterized for the on-pathway dimers of ΔN6-β 2 m and are unable to assemble into amyloid. Instead, the crosslinked D76N-β 2 m dimers are potent inhibitors of amyloid formation, preventing primary nucleation and elongation/secondary nucleation when added in substoichiometric amounts with D76N-β 2 m monomers. The results highlight the specificity of early protein-protein interactions in amyloid formation and show how mapping these interfaces can inform new strategies to inhibit amyloid assembly., Competing Interests: Conflict of interest The authors declare there they have conflict of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alpha-synuclein (αSyn) is a protein involved in neurodegenerative disorders including Parkinson's disease. Amyloid formation of αSyn can be modulated by the 'P1 region' (residues 36-42). Here, mutational studies of P1 reveal that Y39A and S42A extend the lag-phase of αSyn amyloid formation in vitro and rescue amyloid-associated cytotoxicity in C. elegans. Additionally, L38I αSyn forms amyloid fibrils more rapidly than WT, L38A has no effect, but L38M does not form amyloid fibrils in vitro and protects from proteotoxicity. Swapping the sequence of the two residues that differ in the P1 region of the paralogue γSyn to those of αSyn did not enhance fibril formation for γSyn. Peptide binding experiments using NMR showed that P1 synergises with residues in the NAC and C-terminal regions to initiate aggregation. The remarkable specificity of the interactions that control αSyn amyloid formation, identifies this region as a potential target for therapeutics, despite their weak and transient nature., (© 2022. The Author(s).)

Photobiomodulation has been used to inactivate bacterial growth, in different laser or LED protocols. Thus, the aim of this study was to verify the inhibition of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, in ATCC strains and bacteria collected from patients with skin burns, after irradiation with LED; 300 μl of saline solution with bacterial suspension was irradiated at a concentration of 0.5-0.63, by the McFarland scale, after five serial dilutions, with evaluation of pre- and post-irradiation pH and temperature control. The cultures were placed in a bacteriological incubator at 37 °C for 24 h for later counting of colony-forming units (CFU). Data were analyzed by Shapiro-Wilk tests and single-factor ANOVA, with Tukey post hoc (p < 0.05). Both wavelengths and energy densities tested showed inhibition of bacterial growth. The comparison of the irradiated groups (ATCC) with the control group showed the following: S. aureus and P. aeruginosa 465 nm (40 J/cm 2 ) and 630 nm (50 J/cm 2 ) and E. coli 465 nm (40 J/cm 2 ) and 630 nm (30 J/cm 2 ). Among the ATCC S. aureus groups, there was a difference for 630 nm (30 J/cm 2 ) and 465 nm (30, 40, 50 J/cm 2 ). The bacteria from the burned patients were S. aureus (30 and 50 J/cm 2 ) and P. aeruginosa (50 J/cm 2 ). We conclude that different bacterial strains were reduced into colony-forming units after LED irradiation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D., (© 2022. The Author(s).)

Background: Redlining was a racialized zoning practice in the U.S. that blocked fair access to home loans during the 1930s, and recent research is illuminating health problems in the current residents of these historically redlined areas. However, this work has not yet been holistically summarized. Here, we present the first systematic review and meta-analysis comparing health outcomes in redlined versus non-redlined neighborhoods in U.S. cities., Methods: We extracted relevant articles in PubMed, Web of Science, Cochrane and Science Direct databases published from January 2010 to September 2021., Results: The search revealed 12 studies on preterm births (n = 3), gunshot-related injuries (n = 2), cancer (n = 1), asthma (n = 1), self-rated health (n = 1), multiple health outcomes (n = 2), heat-related outcomes (n = 1) and COVID-19 incidence and mortality (n = 1). A meta-analysis of three studies found the odds of having preterm birth was significantly higher (OR = 1.41, 95% CI: 1.05, 1.88; p = 0.02) among women living in redlined areas compared to those in non-redlined areas. Review of other outcomes revealed that gunshot-related injuries, asthma, heat-related outcomes, and multiple chronic conditions were worse in redlined areas, while associations with cancer varied by cancer type. In terms of cause-specific mortality, one study revealed no link between residential redlining and infant mortality rate, while one study on COVID-19 outcomes was inconclusive., Conclusions: Overall, this review presents evidence that living in historically redlined areas is associated with increased risk of multiple serious adverse health outcomes. Further research on mechanisms, remediation, and neighborhood-level interventions is needed to strengthen the understanding of the impacts of redlining on health., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19., Methodology: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured., Results: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients., Conclusions: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2022 Roberto Ovilla-Martinez, Xochitl Cota-Rangel, Jose De La Pena-Celaya, Mariana Alejandra Alvarado-Zepeda, Alejandro Jimenez Sastre, Humberto Azuara Forcelledo, Bernardino Ordonez Rodriguez, Juan Pulido Broca, Aaron Molina Jaimes, Alejandro Muniz-Carvajal, Maria Magdalena Bahena Garcia, Eduardo Cervera Ceballos, Nidia Paulina Zapata Canto, Jorge Oscar Garcia Mendez, Omar Noel Garcia Jimenez, Jesus Alberto Salas Heredia, Javier Solis Soto, Ruben Alberto Villalobos Mendez, Gregorio Ignacio Ibarra, Cindy Ledesma de la Cruz, Nora Araujo Martinez, Jessi Juarez Lara, Cecilio Omar Ceballos Zuniga, Felipe Vicente Villasenor Perez, Jose Carlos Herrera Garcia, Patricia Nuche Salazar, Alfredo Dominguez Paregrina, Bertha Arizpe Bravo, Gabriela Enciso Figueroa, Teresita Trujillo, Adriana Miguel Alvarez, Diego de Jesus Garcia Gallegos, Alejandro Ortiz Arroyo, Claudia Ivette Solorzano Soto, Hiram Javier Jaramillo Ramirez, Ibis De la Cruz Hernandez, Sergio De Gante Martinez, Guadalupe Esmeralda Montesinos Gomez, Silvia Martinez Velasco, Roberto Garcia Graullera, Miguel Angel Vazquez Lopez, Victor Itai Urbalejo Ceniceros, Yolanda Lugo Garcia, Ana Itamar Gonzalez Avila, Jorge Duque Rodriguez, Rodolfo Ruiz Lujan, Violeta I Rodriguez Rivera, Lucio Soberanes Ramirez, Pamela Elena Baez-Islas.)

Introduction: The recalcitrant nature of patients with acute exacerbation of chronic rhinosinusitis (AECRS) potentially involves persisting colonization of the sinonasal mucosa by bacterial biofilms. Biofilms are known to be highly resistant to antibiotics, which may trigger or maintain chronic inflammation in the sinonasal mucosa. However, little is known about the relationship between the minimum inhibitory concentration (MIC) and antibiofilm concentrations of bacteria obtained from AECRS patients., Material and Methods: Thirty bacterial strains from 25 patients with AECRS were identified and underwent MIC determination (VITEK ® 2). The planktonic isolates were submitted to an in vitro formation of biofilms (Modified Calgary Biofilm Device) and determination of minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC) for amoxicillin, amoxicillin/clavulanic acid, clarithromycin, and levofloxacin. MIC of the planktonic forms was compared with MBIC and MBEC levels, according to the breakpoints established by the Clinical Laboratory Standards Institute guidelines., Results: The main bacteria retrieved was S. aureus (60%), followed by other Gram-positive and Gram-negative bacteria in lower frequencies. 76.7% of strains formed biofilm in vitro (n=23/30). The planktonic isolates presented high rates of resistance for amoxicillin (82.6%) and clarithromycin (39.1%), and lower rates for amoxicillin/clavulanic acid (17.4%). The biofilm-forming bacteria counterparts presented higher levels of MBIC and MBEC compared to the MIC levels for amoxicillin, amoxicillin/clavulanic acid, and clarithromycin. Levofloxacin was highly effective against both planktonic and biofilm forms. Planktonic resistant forms were associated with levels of antibiofilm concentrations (MBIC and MBEC)., Conclusions: Biofilm-forming bacteria from AECRS patients are prevalent, and biofilm forms are highly resistant to antibiotics compared to their planktonic counterparts. Antibiotic resistance observed in planktonic forms is a good indicator of biofilm resistance, although near 20% of susceptible planktonic bacteria can produce antibiotic tolerant biofilms., 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 © 2022 Sabino, Valera, Santos, Fantucci, Titoneli, Martinez, Anselmo-Lima and Tamashiro.)

Background: Worldwide, healthcare facilities face high and often inappropriate consumption of antimicrobials. However, there are limited antimicrobial stewardship (ASP) studies from low- and middle-income countries that include restrictive measures and their impacts on antimicrobial consumption., Aim: This study aims to assess the impact of a restrictive bundle (preauthorization requirements and offering consultation with an infectious diseases physician 24 hours a day) on antimicrobial consumption, in a tertiary hospital in Brazil., Methods: We conducted an interrupted time series analysis (ITS) with pharmacy-based data from January 2010 to December 2018 to evaluate changes of level and slope in antimicrobial consumption (expressed in DDD/1,000 patient-days) after the implementation of the restrictive bundle in September 2014. Fourteen restricted antimicrobials (amphotericin B deoxycholate, liposomal amphotericin B, micafungin, voriconazole, ganciclovir, amikacin, ampicillin/sulbactam, daptomycin, ertapenem, levofloxacin, linezolid, piperacillin/tazobactam, polymyxin B, and tigecycline) and eight unrestricted were analysed., Findings: Among the 14 restricted antimicrobials, four presented a significant negative level change: micafungin (-2,14, p=.027), voriconazole (-14.72, p<.001), ertapenem (-1.89, p=.007) and amikacin (-13.98, p<.001). The only negative slope change was observed for the liposomal amphotericin B, -0.532 (p=.009). The restricted antibiotics group presented an increased consumption trend (1.068, p=.002) compared to the pre-intervention period, a similar change was observed for the unrestricted antibiotics group (1.360, p<.001)., Conclusion: Preauthorization and 24 hour expert consultation were partially effective as a restrictive antimicrobial stewardship bundle in a Brazilian tertiary-care hospital. Increased consumption of unrestricted antimicrobials was observed as a side effect of the intervention., (© 2022 The Authors.)

Neurocryptococcosis, a meningoencephalitis caused by Cryptococcus spp, is treated with amphotericin B (AmB) combined with fluconazole. The integrity of the brain-blood barrier and the composition of the cerebrospinal fluid (CSF) may change due to infectious and/or inflammatory diseases such as neurocryptococcosis allowing for the penetration of AmB into the central nervous system. The present study aimed to develop LC-MS/MS methods capable of quantifying AmB in CSF at any given time of the treatment in addition to plasma, plasma ultrafiltrate, with sensitivity compatible with the low concentrations of AmB reported in the CSF. The methods were successfully validated in the four matrices (25 μl, 5-1,000 ng ml -1 for plasma or urine; 100 μl, 0.625-250 ng ml -1 for plasma ultrafiltrate; 100 μl, 0.1-250 ng ml -1 for CSF) using protein precipitation. The methods were applied to investigate the pharmacokinetics of AmB following infusions of 100 mg every 24 h for 16 days administered as a lipid complex throughout the treatment of a neurocryptococcosis male patient. The methods allowed for a detailed description of the pharmacokinetic parameters in the assessed patient in the beginning (4th day) and end of the treatment with AmB (16th day), with total clearances of 7.21 and 4.25 L h -1 , hepatic clearances of 7.15 and 4.22 L h -1 , volumes of distribution of 302.94 and 206.89 L, and unbound fractions in plasma ranging from 2.26 to 3.25%. AmB was quantified in two CSF samples collected throughout the treatment with concentrations of 12.26 and 18.45 ng ml -1 on the 8th and 15th days of the treatment, respectively. The total concentration of AmB in plasma was 31 and 20 times higher than in CSF. The unbound concentration in plasma accounted for 77 and 44% of the respective concentrations in CSF. In conclusion, the present study described the most complete and sensitive method for AmB analysis in plasma, plasma ultrafiltrate, urine, and CSF applied to a clinical pharmacokinetic study following the administration of the drug as a lipid complex in one patient with neurocryptococcosis. The method can be applied to investigate the pharmacokinetics of AmB in CSF at any given time of the treatment., 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 Pippa, Marques, Silva, Vilar, de Haes, Fonseca, Martinez, Coelho, Wichert-Ana and Lanchote.)

In the tyrosine kinase inhibitor era, the blast phase of chronic myeloid leukaemia (BP-CML) renders an uncommon presentation and has a poor prognosis with an estimated overall survival below 20%. Mixed-phenotype blast phase is even more infrequent, presenting in 3.3% of these patients. Blast phase manifests along haematological sarcomas, with extramedullary activity in lymph nodes, skin and bone. We report the case of a patient with an ovarian sarcoma as an extramedullary presentation of mixed-phenotype BP-CML refractory to conventional treatment which responded to immunotherapy against CD33 and CD19., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis . Compounds including a sulfur-containing scaffold have been shown to be key scaffolds in various antituberculosis agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids 11a-j have, to the best of our knowledge, not been previously described as antituberculosis agents., Purpose: In the present study, we investigated the role of substituents attached to the phenyl ring of a 3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds 11a-j ) in inhibiting the growth of M. tuberculosis strain H37Rv., Methods: (Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids 11b-j , with R groups including various electron-donating or electron-withdrawing groups, were designed by structurally modifying the lead compound 11a . The syntheses of 11a-j involved each one-step procedure starting from the corresponding substituted acetophenone. Compounds 11a-j were tested against M. tuberculosis strain H37Rv to evaluate their bacterial growth inhibitory activities. ADMET profiles were predicted by employing three different methods. In addition, molecular docking studies were carried out, based on the molecular similarities of the synthesized compounds with ethionamide ( 5 ), on the active site of the M. tuberculosis H37Rv (3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer., Results: The antituberculosis activities of compounds 11a-j could be explained in terms of the presence of electron-donating or electron-withdrawing substituents on the aromatic ring of the substituted 3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and selectivity index (SI) value of ( Z )-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid 11e suggested that this compound could be used for the design of novel antituberculosis agents. Most of the synthesized molecules showed an acceptable ADME profile and a low probability of being toxic. Docking studies of 11d and 11e showed them forming hydrogen bonds with the ACys61 residue of the HadAB enzyme., Conclusion: Our results suggested that the antituberculosis compound 11e could be used for the design of novel antituberculosis agents., Competing Interests: The authors declare no conflicts of interest, financial or otherwise., (© 2021 Pretelín-Castillo et al.)

Introduction: The clinical manifestations of cryptococcosis are usually associated with the infecting agents Cryptococcus neoformans (CN) and C. gattii (CG) species complexes and the host. In this study, non-HIV-infected patients, at a university hospital in southeastern Brazil, had epidemiological and clinical data associated with cryptococcal disease and isolated Cryptococcus species: CN - 24 patients and CG - 12 patients., Methods: The comparison was comprised of demographic data, predisposing factors, clinical and laboratory manifestations, and outcomes of cryptococcosis patients treated between 2000 and 2016. Immunocompetent and immunosuppressed patients were also compared, irrespective of the infecting species. Cryptococcus spp. were genotyped by PCR-RFLP analysis of the URA5 gene., Results: Infections by the CN species complex (100% VNI genotype) were associated with drug immunosuppression and fungemia, and patients infected with the CG species complex (83% VG II and 17% VGI genotypes) had more evident environmental exposure and higher humoral response. CN and CG affected patients with or without comorbidities., Conclusions: Diabetes mellitus, other chronic non-infectious diseases, and alcoholism were likely predisposing factors for infection by both CN and CG species. Immunocompetent patients, independent of the infecting Cryptococcus species complexes, showed a higher occurrence of meningitis and a trend toward less fungal dissemination and longer survival than immunosuppressed hosts.

Purpose: In-house Paracoccidioides spp. antigens are commonly used in the serological diagnosis of paracoccidioidomycosis (PCM). The sensitivity and specificity of a commercial Paracoccidioides spp. antigen was assessed for PCM serological testing., Method: Counterimmunoelectrophoresis and double immunodiffusion were used to evaluate the Paracoccidioides ID Antigen® reagent in sera from PCM cases and patients with other diseases., Results: All active PCM sera (n=24) were reactive using counterimmunoelectrophoresis (sensitivity = 100%), including 11 cases of infection by P. brasiliensis sensu stricto and one by P. americana. Fifteen (88%) out of 17 sera from patients on treatment or cured were reactive, including one case of P. lutzii infection. One to three bands of antigen-antibody precipitate were observed on the agarose gel, with a predominance of two to three bands in the test with untreated PCM sera or at the beginning of antifungal therapy. All sera from patients with histoplasmosis (n=7), aspergillosis (n=5), and other diseases (n=27) tested negative (specificity = 100%). The overall sensitivity and specificity using the commercial antigen and double diffusion test were 75% and 100%, respectively., Conclusion: The commercial antigen performed satisfactorily and may contribute to the dissemination of the use of serological tests for the PCM diagnosis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Antimicrobial resistance has worsened since the onset of COVID-19., Methods: This study involved patients admitted to the adult intensive care unit (ICU) of a tertiary hospital. Pre- and post-COVID-19 data were analyzed. The healthcare-related infections (HCRIs) reported between January 2018 and January 2020 and during the pandemic between February and July 2020 were compared., Results: Antimicrobial resistance increased during the pandemic, especially for Klebsiella pneumoniae isolates, with a rate increase from 5% to 50% for Polymyxin B., Conclusions: The susceptibilities of the main pathogens associated with HCRIs in the ICU changed and should be considered in managing severe COVID-19.

Introduction: Frontal sinus fracture management continues to be a point of controversy. Many systematic reviews have been done, but meta-analyses comparing various approaches to frontal sinus fractures are scarce. Our study focuses on open surgical repair versus endoscopic repair of frontal sinus fractures., Materials and Methods: A MEDLINE search was performed to identify prospective RCTs, non-RCTs, guidelines, case-control, and observational studies published in English before April 2019. Search terms included (1) frontal sinus, (2) skull fractures, (3) frontal bone, alone or in combination. An in-depth review was conducted to identify publications relevant to this analysis. Studies that included pediatric patients, case reports, and review articles without original data were excluded. Postoperative outcomes included were cosmesis, sinus function, mucocele, sinusitis, cerebrospinal fluid leak, meningitis, and brain abscess. Meta-analysis of proportions, Fisher exact test, and relative risks were calculated., Results: Seven studies were ultimately included in the meta-analysis. The assessment of heterogeneity indicated that the studies are comparable. The weighted outcome proportions of patients with postoperative cosmetic deformity and mucocele are found to be significantly higher in patients who underwent open repair compared to patients who received endoscopic treatment. No significant difference between the 2 intervention groups in regards to the other outcomes., Conclusion: Based on this meta-analysis, no definitive conclusions regarding superiority of one approach over the other can be made. There are currently no universally accepted algorithms that aid in the decision to proceed with either approach. It is likely that these 2 techniques will come to serve different roles in treatment, as they can each be utilized to achieve different goals. At this time, the only recommendation is to proceed with whichever technique can be safely performed based upon surgeon experience and fracture pattern., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Candida spp. are the main causative agents of invasive fungal infections in immunocompromised patients. Candidemia has attributable mortality rates of 15 to 35% and increases hospitalisation time and costs, thus making this disease a public health concern. This study aimed to use pulsed-field gel electrophoresis (PFGE), microsatellite length polymorphism (MLP) and multilocus sequence typing (MLST) to analyse the genetic relationships among 65 Candida spp. bloodstream isolates, including 35 Candida albicans, 15 Candida glabrata and 15 Candida tropicalis isolates, all of which were obtained from patients in a Brazilian hospital. Moreover, patient clinical data were assessed. All techniques resulted in high discriminatory indexes. C. albicans and C. tropicalis isolates showed high genetic variability, while C. glabrata isolates had relatively low genetic variability. Moreover, a cluster of C. glabrata isolates was identified in a hospital unit. New MLST sequence types, diploid sequence types and alleles are described. Relationships were not observed between the molecular typing results and clinical characteristics. The molecular typing of clinical strains increases our understanding of candidemia epidemiology and promotes the development of strategies that can reduce the incidence of this disease. Moreover, this study is the first to combine these techniques to genotype these three species in Brazil.

Background: Cryptococcus neoformans/ Cryptococcus gattii species complex is composed of encapsulated yeast species that are causative agents of cryptococcosis. The characterisation of pathogenic Cryptococcus species provides useful data for epidemiological studies as well as the clinical diagnosis and treatment of patients., Objectives: This study aimed to characterise the epidemiology, antifungal susceptibility and virulence of 72 clinical strains isolated from cryptococcosis cases between 2012 and 2017 in a tertiary reference hospital in south-eastern Brazil., Methods: Species and molecular types were molecularly assessed by PCR and PCR-restriction fragment length polymorphism (RFLP) of the URA5 gene. Antifungal susceptibility testing was performed according to the CLSI protocols. The virulence was studied in a Galleria mellonella infection model., Results: The most frequently isolated strain was C. neoformans molecular type VNI (61/72; 84.7%), although C. neoformans molecular type VNII (3/72; 4.2%) was also isolated. Additionally, C. deuterogattii molecular type VGII (8/72; 11.1%) was present, but most frequently from non-HIV-infected patients. Non-wild-type phenotype to the antifungals was observed in 26.4% (19/72) of the C. neoformans and C. deuterogattii clinical isolates, and the latter demonstrated higher MIC to fluconazole and itraconazole than C. neoformans clinical isolates. Finally, the virulence of C. neoformans and C. deuterogattii clinical isolates was diverse in G mellonella larvae and uncorrelated with the virulence factors of melanin and capsule., Conclusions: The assessment of the spread of cryptococcal species and molecular types as well as the pattern of corresponding antifungal susceptibility and virulence aids in surveil the emergence of resistant strains, ensuring more accurate management of the cryptococcal infection., (© 2020 Wiley-VCH GmbH.)

Paracoccidioidomycosis caused by Paracoccidioides lutzii is endemic in the Midwest of Brazil and its clinical spectrum is still little known due to the recent identification of this fungal species. A patient resident in Southeast Brazil, but who had lived for many years in the Midwest region, presented with skin injuries, chronic cough and bilateral adrenal involvement. Paracoccidioides spp. was isolated in culture from a skin lesion biopsy. This isolate was later identified as P. lutzii using gene sequencing. A favorable initial response to treatment with itraconazole was observed, but a few weeks later, the patient developed respiratory failure and worsening of lung lesions. Evaluation by computed tomography and echocardiography were suggestive of pulmonary arterial hypertension, and a bronchoscopic biopsy showed peribronchial remodeling. The patient completed the antifungal treatment but maintained the respiratory dysfunction. The reported case shows that P. lutzii can be isolated from patients in a geographic area far from the place of infection acquisition and that, as P. brasiliensis , it can cause adrenal injury and cardio-respiratory complications as a consequence of excessive necrosis and fibrosis.

The Tepary bean ( Phaseolus acutifolius ) lectin fraction (TBLF) exhibits differential cytotoxicity on colon cancer cells and inhibition of early tumorigenesis in the colon (50 mg/kg, three times per week, for 6 weeks). TBLF showed low toxicity with the ability to activate the immune system; however, some adverse effects are the loss in body weight gain, intestinal atrophy, and pancreatic hyperplasia. After a recovery period of 2 weeks after treatment, reversion of pancreatic hyperplasia but no recovery of intestinal atrophy was observed. As TBLF has shown anticancer effects on the colon, it is important to characterize the adverse effects and how they can be reversed. Sprague Dawley rats were administered with TBLF (50 mg/kg) for 6 weeks, three times per week, and then allowed to recover for 6 weeks post-treatment. After TBLF administration, small intestine atrophy, villus atrophy, and cryptic hyperplasia were confirmed, as well as increased intestinal mucus production, increased permeability and a decrease in the apparent ileal digestibility of crude proteins. The colon showed damage in the simple prismatic tissue and decreased crypt depth, and changes in microbiota and a decrease in the apparent fecal digestibility of crude protein were determined. Our results show that the adverse effects provoked by TBLF were partially reversed after 6 weeks of recovery post-treatment, suggesting that increasing the recovery period it could be possible to reverse all adverse effects observed., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The cosmetic use of devices like prostheses to increase breast volume is nothing new. It is calculated that millions of people have been exposed to silicone in several ways, including breast implants, and since 1964 there has been uncertainty regarding their safety. We did not find in the literature any studies that reported the appearance of a specific immunological disease in patients with silicone breast implants. Furthermore, there are also neither case-control studies nor reports of patients proving that symptoms of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) occurred after the placement of silicone implants nor that the patients had pre-existing symptoms. Several studies link silicone to allergic reactions and the development of systemic autoimmune diseases; however, other studies deny this association. There are currently several theories about the effect of silicone on the body. One theory with greater acceptance proposes an adjuvant effect of silicone on the development of autoimmune diseases in genetically predisposed patients. However, the variety of symptoms occurring in patients who develop these pathologies leads to doubts about the relationship between the adjuvant effects of a silicone prosthesis may have with a specific autoimmune disease or a mix of these diseases. The lack of consensus on this topic obliges a full review of what has already been reported in the literature to integrate the knowledge and propose a focus for new research on this matter. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The D76N variant of human β 2 -microglobulin (β 2 m) is the causative agent of a hereditary amyloid disease. Interestingly, D76N-associated amyloidosis has a distinctive pathology compared with aggregation of WT-β 2 m, which occurs in dialysis-related amyloidosis. A folding intermediate of WT-β 2 m, known as the I T -state, which contains a nonnative trans Pro-32, has been shown to be a key precursor of WT-β 2 m aggregation in vitro However, how a single amino acid substitution enhances the rate of aggregation of D76N-β 2 m and gives rise to a different amyloid disease remained unclear. Using real-time refolding experiments monitored by CD and NMR, we show that the folding mechanisms of WT- and D76N-β 2 m are conserved in that both proteins fold slowly via an I T -state that has similar structural properties. Surprisingly, however, direct measurement of the equilibrium population of I T using NMR showed no evidence for an increased population of the I T -state for D76N-β 2 m, ruling out previous models suggesting that this could explain its enhanced aggregation propensity. Producing a kinetically trapped analog of I T by deleting the N-terminal six amino acids increases the aggregation rate of WT-β 2 m but slows aggregation of D76N-β 2 m, supporting the view that although the folding mechanisms of the two proteins are conserved, their aggregation mechanisms differ. The results exclude the I T -state as the origin of the rapid aggregation of D76N-β 2 m, suggesting that other nonnative states must cause its high aggregation rate. The results highlight how a single substitution at a solvent-exposed site can affect the mechanism of aggregation and the resulting disease., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Smith et al.)

Paracoccidioides brasiliensis complex and P. lutzii are the etiological agents of paracoccidioidomycosis. The geographic distribution of these species in South America is still poorly comprehended. Fifty samples of Paracoccidioides spp. were genotyped, with 46 clinical isolates predominantly isolated in the geographic area of Ribeirão Preto, SP, and four environmental isolates collected in Ibiá, MG, southeastern Brazil. These isolates were evaluated by PCR-RFLP (Restriction Fragment Length Polymorphism) of the tub 1 gene and the sequencing of the gp43 exon 2 loci. The species P. lutzii was confirmed by sequencing the internal transcribed spacer (ITS) region of the ribosomal DNA. P. brasiliensis sensu stricto S1b ( n = 42) and S1a ( n = 5), P. americana ( n = 1), P. restrepiensis ( n = 1), and P. lutzii ( n = 1) were identified among the clinical isolates. All the environmental isolates were characterized as P. brasiliensis sensu stricto S1b. The patient infection by P. lutzii , P. americana (PS2), and one isolate of P. brasiliensis sensu stricto S1b most likely occurred in a geographic area far from the fungal isolation site. No association was found between the infecting genotype and the disease form. These results expand the knowledge of the Paracoccidioides species distribution and emphasize that human migration must also be considered to pinpoint the genotypes in the endemic area.

Background: A significant difference exists between the published results reporting the clinical outcome following brain arteriovenous malformation (AVM) ruptures. Information about the outcome following hemorrhage in an AVM population treated with radiosurgery could provide additional information to assess the risk of mortality and morbidity following an AVM hemorrhage., Methods: Clinical outcome was studied in 383 patients, the largest patient population yet studied, who suffered from a symptomatic hemorrhage after Gamma Knife® surgery (GKS) but before confirmed AVM obliteration. The impact of different patient, AVM, and treatment parameters on the clinical outcome was analyzed. The aim was to generate outcome predictions by comparing our data to and combining them with earlier published results., Results: No relation was found between clinical outcome and treatment parameters, indicating that the results are applicable also on untreated AVMs. Twenty-one percent of the patients died, 45% developed or experienced worsening of neurological sequelae, and 35% recovered completely after the hemorrhage. Old age was a predictor of poor outcome. Sex, AVM location, AVM volume, and history of prior hemorrhage did not influence the outcome. The mortality rate was comparable to earlier published prospective data, but higher than that found in retrospective studies., Conclusions: The mortality rates in earlier published retrospective series as well as in studies focusing on clinical outcome following AVM hemorrhage significantly underestimate the risk for a mortal outcome following an AVM hemorrhage. Based on our findings, an AVM rupture has around 20% likelihood to result in mortality, 45% likelihood to result in a minor or major deficit, and 35% likelihood of complete recovery. The findings are probably applicable also for AVM ruptures in general. The cumulative mortality and morbidity rates 25 years after diagnosis were estimated to be around 40% in a patient with a patent AVM.

A new method, simple and fast, for fluconazole (FLU) quantification in cerebrospinal fluid (CSF) samples using dispersive liquid-liquid microextraction (DLLME) and an eco-friendly mobile phase for HPLC-PDA was developed. The study of DLLME extraction condition covered the investigation of 12 combinations of extraction and disperser solvents followed by a fractional factorial design 2(7-3) to determine the influence of seven factors. After this stage, a central composite design was performed for three factors and a response surface was obtained. Aiming a compromise between a good recovery and a low organic solvent use it was established an extraction condition that consists of: 100 μL of chloroform, 100 μL of isopropyl alcohol, 200 μL of CSF, 200 μL of 50 mM phosphate buffer pH 7.3 and centrifugation for 5 min at 2200g and 4 °C. The HPLC analysis used an Ascentis® Express C18 column (100 mm × 4.6 mm, 2.7 μm) and an Ascentis® Express C18 guard column (3 mm × 4.6 mm, 2.7 μm), ethanol : water (15 : 85, v/v) as mobile phase, temperature of 45 °C, flow rate of 0.8 mL min-1 and phenacetin as internal standard. The method validation was performed according to European Agency's Guideline on Bioanalytical Validation Methodology and a linear range was obtained from 0.25 to 62.5 μg mL-1, with precision and accuracy within the recommended limits and recovery of 70% for FLU and 81% for phenacetin. Samples were stable in the studies performed and the method showed to be selective and with no carryover effect. The feasibility of the obtained method was confirmed by FLU determination at a CSF from a patient who was treated for neuromycosis. Therefore, here is described a method that meets many principles of green analytical chemistry and is useful for FLU therapeutic monitoring.

Phylogenetic species of Paracoccidioides brasiliensis complex (S1a and S1b, PS2, PS3, and PS4) and Paracoccidioides lutzii are agents of paracoccidioidomycosis, an endemic fungal disease in Latin America. P. restrepiensis (PS3 genotype) was classified as monophyletic and geographically restricted to Colombia and neighboring territories. BAT (or Pb-327B) was isolated from a patient living in the southeast region of Brazil but with genotype similar to Colombian Paracoccidioides spp. strains. This study aimed to define the phylogenetic species of BAT isolate by using additional genotyping methods, as well as reviewing the epidemiological and clinical studies related to P. restrepiensis isolates. Genomic DNA of BAT isolate and reference strains of P. brasiliensis sensu stricto (S1b), P. americana (PS2), P. restrepiensis (PS3), and P. lutzii were analyzed by conventional polymerase chain reaction (PCR) of partial gp43 exon 2 loci, by PCR-RFLP technique of tub1 gene, and by sequencing of the whole gp43 exon 2 loci. Here, we show that BAT isolate belongs to P. restrepiensis species, which is an unusual identification in southeastern Brazil, where P. brasiliensis sensu stricto is the prevalent genotype. This identification has relevance for geographical distribution and propagation of the genus Paracoccidioides in South America.

Expertise in the delivery of effective local analgesia is critical to the success of in-office procedures. Here's how to optimize patient outcomes and satisfaction.

The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative cross-coupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.

Aggregation of human α-synuclein (αSyn) is linked to Parkinson's disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this 'master controller' prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function-a region that could be targeted to prevent aggregation in disease.

Introduction: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug., Methods: : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1)., Results: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died., Conclusions: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.