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Background: American trypanosomiasis, commonly referred to as Chagas disease, is caused by a single cell protozoan known as Trypanosoma cruzi (T. cruzi). Although those affected are mainly in Latin America, Chagas has been detected in the United States (US), Canada and in many European countries due to migration. Few studies have explored the epidemiology of Chagas within the US or changes in disease burden over the past decade. The objective of this study was to explore the trends and associated characteristics for Chagas disease among hospitalized women of reproductive age in the US. Methods: We analyzed admissions data including socio-demographic and hospital characteristics for inpatient hospitalization for women of reproductive age (15–49 years) in the US from 2002 through 2017. We employed Joinpoint regression analysis to determine trends in the prevalence of Chagas disease over this period. Results: A total of 487 hospitalizations of Chagas disease were identified, corresponding to 3.7 per million hospitalizations over the study period. The rate statistically increased from 1.6 per million in 2002 to 7.6 per million hospitalizations in 2017. Chagas was most prevalent among older women, Hispanics and those in the highest zip income bracket. The in-hospital mortality rate was about 10 times greater among women with Chagas compared to those without the condition (3.1% versus 0.3%), and the condition tended to be clustered in women treated at large, urban teaching hospitals in the Northeastern region of the US. Conclusion: Chagas disease diagnosis appears to be increasing among hospitalized women of reproductive age in the US with a 10-fold elevated risk of mortality.

Background: Infective endocarditis continues to be a significant concern and may be undergoing an epidemiological transition. Methods: Were studied 1804 consecutive episodes of infective endocarditis between 1978 and 2022. The mean age was 48 ( ± 19), and 1162 (64%) patients were male. Temporal trends in demographic data, comorbidities, predisposing conditions, microorganisms, complications and in-hospital death have been studied over the decades (1978–1988, 1989–1999, 2000–2010 and 2011–2022). The outcomes and clinical characteristics were modeled using nonlinear cubic spline functions. Findings: Valve surgery was performed in 50% of the patients and overall in-hospital mortality was 30%. From the first to the fourth decade studied, the average age of patients increased from 29 to 57 years (p

Campi Flegrei caldera is an Italian high-risk volcano experiencing a progressively more intense long-term uplift, accompanied by increasing seismicity and geochemical emissions over the last two decades. Ground deformation shows an axisymmetric bell-shaped pattern, with a maximum uplift of about 120 cm, from 2005, in the caldera central area. We analyzed Sentinel-1 and COSMO-SkyMed Multi-Temporal DInSAR measurements and GNSS data to reveal and investigate a geodetic anomaly that has clearly manifested since 2021, locally deviating from the typical bell-shaped deformation pattern. This anomaly is located east of Pozzuoli town, in the Mt. Olibano–Accademia area, covers an area of about 1.3 km2 and shows, in comparison to surrounding areas, a maximum uplift deficit of about 9 cm between 2021 and 2023. To investigate the anomaly causes, we analyzed the caldera seismicity and inverted the DInSAR data to determine the primary source of the ground deformation pattern, which is consistent with a penny-shaped source located approximately 3800 m beneath the Pozzuoli town, with a radius of about 1200 m. We also found that the time evolution of the uplift deficit in the geodetic anomaly area correlates well with the earthquake occurrence, with the greater magnitude events clustering in this area. These considerations suggest the geodetic anomaly is a local response to the tensile stress regime produced by the inflating primary deformation source. This phenomenon can be influenced by the Mt. Olibano–Accademia lava domes lithological heterogeneities that may induce a localized reaction to ground deformation during the inflationary phase. Our interpretation aligns with the concentration of earthquakes and hydrothermal fluid emissions in this area, indicating the presence of faults, fractures, and fluid circulation. Accordingly, the geodetic anomaly area represents a zone of crustal weakness that requires careful monitoring and study.

Co-precipitation of γ′ and γ′′ is the main strengthening mechanism that provides superior high-temperature strength in directly aged Alloy 718 aerospace parts. Control of their morphology, fraction, and configuration might allow exposure to more demanding operation environments in next-generation aircraft engines. The density of geometrically necessary dislocations introduced during hot deformation has been shown to significantly affect the co-precipitate morphology of γ′ and γ′′ in materials free of the δ-phase. However, the combined effects of geometrically necessary dislocation density and lower Nb content due to higher δ-phase fractions on co-precipitation behaviour and strengthening remain unknown. We verify these effects by hardness testing as a proxy for high-temperature strength in materials with 4.1 % δ-phase fraction. Deformation at 950 °C yields a remarkable increase of 12 % in hardness after direct ageing, explained by the prevalence of complex co-precipitate configurations. Deformation at 1000 °C decreases the δ-phase fraction and geometrically necessary dislocation density but achieves up to 19 % volume fractions of γ″, leading to a predominance of monoliths and duplet co-precipitates and a better direct ageing response. Atom probe microscopy reveals the flux of elements during co-precipitation. We recommend a δ-annealing treatment before the final forging step for manufacturing stronger Alloy 718 aerospace parts.

Introdução: Endocardite infecciosa é uma doença pouco frequente mas com elevado risco de complicações e morte. Objetivo: Descrever tendências temporais nas características clínicas e epidemiológicas de pacientes hospitalizados com endocardite infecciosa em um único centro de referência ao longo de quatro décadas. Métodos: Coorte de 1.804 episódios consecutivos de endocardite em pacientes (> 12 anos) internados em um hospital cardiológico, 1978-2022. O desfecho foi óbito intra-hospitalar. Foram estudados dados demográficos, comorbidades, condições predisponentes, microrganismos e complicações ao longo do tempo e por décadas (1978-1988, 1989-1999, 2000-2010, 2011-2022). Foi realizada uma análise de séries temporais, modelando cada ano usando uma função spline cúbica não-linear com 4 pontos de inflexão para permitir a análise de não-linearidades ao longo do tempo. As associações brutas de cada resultado com essa função não-linear dos anos foram analisadas e ajustadas para fatores de risco (idade, prótese valvar, S. aureus, evento embólico e abscesso perivalvar). Resultados: A maioria dos pacientes era do sexo masculino (64%). Verificou-se aumento da mediana de idade ao longo das décadas (29 a 57 anos; p < 0,001). Também se observou redução na frequência de cardiopatia reumática (14% para 6%; p < 0,001) assim como das infecções estreptocócicas (46% para 33%; p < 0,001). Houve um aumento progressivo de endocardite em prótese valvar, complicações associadas (abscesso perivalvar, insuficiência cardíaca descompensada, embolização) e infecções por estafilococos coagulase-negativos e MRSA ao longo do tempo. A mortalidade geral intra-hospitalar foi de 30%, com tendência ascendente ao longo das últimas três décadas (p = 0,022). No entanto, ao ajustar para fatores relacionados a pior prognóstico (idade, prótese, infecção por S. aureus, eventos embólicos e abscesso perivalvar), verificou-se uma diminuição nas mortes intra-hospitalares (p = 0,019), variando de 34% na primeira década estudada até 26% na última década. Conclusões: No período de 44 anos, ocorreram mudanças significativas nas características clínicas e epidemiológicas dos pacientes internados com endocardite. Apesar do aumento da idade média dos pacientes, do envolvimento de próteses valvares, das infecções por estafilococos coagulase negativos/MRSA e das complicações, foi observada uma redução progressiva na taxa de mortalidade ajustada aos fatores de risco ao longo das décadas analisadas.

Increasing evidence suggests that Alzheimer’s disease (AD) and Parkinson’s disease (PD) share monoamine and alpha-synuclein (αSyn) dysfunctions, often beginning years before clinical manifestations onset. The triggers for these impairments and the causes leading these early neurodegenerative processes to become AD or PD remain unclear. We address these issues by proposing a radically new perspective to frame AD and PD: they are different manifestations of one only disease we call “Neurodegenerative Elderly Syndrome (NES)”. NES goes through three phases. The seeding stage, which starts years before clinical signs, and where the part of the brain-body affected by the initial αSyn and monoamine dysfunctions, influences the future possible progression of NES towards PD or AD. The compensatory stage, where the clinical symptoms are still silent thanks to compensatory mechanisms keeping monoamine concentrations homeostasis. The bifurcation stage, where NES becomes AD or PD. We present recent literature supporting NES and discuss how this hypothesis could radically change the comprehension of AD and PD comorbidities and the design of novel system-level diagnostic and therapeutic actions.

Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.

Advancements in thermo-mechanical processing of Ni-based superalloys enable manufacturing of engineering parts with superior mechanical properties. Forged aeroengine disks exhibit radial microstructural heterogeneities from both pre-materials and prior processing. Here we correlate microstructural variations in an industrially forged alloy 718 aeroengine disks to their processing history via finite element simulations. We examine a disk intentionally manufactured to exhibit hardness variations. Several radial positions are characterized to reveal twin boundaries and δ phase fractions prior to ageing and grain size, geometrically necessary dislocation (GND) densities, chemical compositions, γ′ and γ′′ precipitates in both as-forged and direct aged conditions. We find that localized meta-dynamic recrystallization causes accelerated grain growth in low hardness regions, while highly strained areas accelerate precipitation of strengthening phases. In these areas, the direct ageing effect is weakened by the presence of non-shearable coarsened γ′′ precipitates. Overall, direct ageing is shown to successfully mitigate radial property heterogeneities. We underpin this by a strengthening model elucidating the direct ageing effect on the reduction of hardness heterogeneity. Variations in grain boundary strengthening, work hardening, and solid solution strengthening after direct ageing have low impact on hardness variations, where precipitation strengthening provides as much as 44% of the strength after direct ageing.

Improving mechanical properties of the Ni-based superalloy Alloy 718, commonly used in turbine discs, is of vital importance to commercial aviation. The need for higher efficiency will push materials to the limit. Modifications in the processing routes of this alloy can be more easily implemented in industry than changes in the alloying elements. Variations in ageing treatment or cooling rate from hot forging can produce a wide variety of mechanical properties. These are mostly caused by changes in the nanoscale precipitates responsible for strengthening. The effects of different common ageing treatments such as conventional and direct ageing on clustering, size, volume fraction, morphology, configuration, and chemical composition of γ′-and γ′′-precipitates are still largely unknown. We investigate these aspects of the precipitates with atom probe microscopy and correlate them with hardness. The flux of the main chemical elements in the formation of co-precipitates such as duplets and triplets is remarkably different in conventionally and directly aged materials. Dislocation rich structures also inflict in unexpected rapid formation of γ′′-precipitates at temperatures more than 90 °C higher than predicted by time–temperature-transformation diagrams. Water quenching from forging impedes precipitates formed along dislocations to coarsen during ageing, considerably impacting hardness, in comparison to air cooling.

In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application.P2Y12R mRNA and IL-1β protein were time-dependently overexpressed in the rat hind paw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-α, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3 mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-1β in the spinal cord. Subdiaphragmatic vagotomy and the α7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1β.Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways.

Introduction: Promoting diversity among faculty, administrators, and librarians in schools and colleges of pharmacy (SCOP) would be beneficial for the recruitment and retention of students from diverse backgrounds. Graduating such diverse pharmacists could assist in reducing healthcare disparities. Promoting diversity requires a climate that is inclusive of people from all backgrounds. The goal of this study was to examine the working environment of historically marginalized faculty, administrators, and librarians within pharmacy education., Methods: An electronic survey was administered to all faculty, administrators, and librarians listed in the American Association of Colleges of Pharmacy roster., Results: Responses from 339 participants were analyzed. Twenty-seven percent of these participants either observed or personally experienced misconduct during the previous five years. When action was taken, it resulted in the cessation of the misconduct only 38% of the time. Respondents most frequently identified the following as ways to make it easier to address misconduct: support from supervisors, support from peers, and education on how to address misconduct., Conclusions: Exclusionary, intimidating, offensive, and/or hostile communication/behaviors towards historically marginalized faculty, administrators, and librarians do exist in SCOP. The academy should work towards promoting diversity, equity, and inclusion in SCOP through education and provide administrative and peer support for reporting and managing professional misconduct., Competing Interests: Declaration of competing interest None., (Published by Elsevier Inc.)

Flue gases are the gases which are produced from industries related to chemical manufacturing, petrol refineries, power plants and ore processing plants. Along with other pollutants, sulfur present in the flue gas is detrimental to the environment. Therefore, environmentalists are concerned about its removal and recovery of resources from flue gases due to its activation ability in the atmosphere to transform into toxic substances. This review is aimed at a critical assessment of the techniques developed for resource recovery from flue gases. The manuscript discusses various bioreactors used in resource recovery such as hollow fibre membrane reactor, rotating biological contractor, sequential batch reactor, fluidized bed reactor, entrapped cell bioreactor and hybrid reactors. In conclusion, this manuscript provides a comprehensive analysis of the potential of thermotolerant and thermophilic microbes in sulfur removal. Additionally, it evaluates the efficacy of a multi-enzyme engineered bioreactor in this process. Furthermore, the study introduces a groundbreaking sustainable model for elemental sulfur recovery, offering promising prospects for environmentally-friendly and economically viable sulfur removal techniques in various industrial applications., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Essentials ERp72 is a thiol isomerase enzyme. ERp72 levels increase at the platelet surface during platelet activation. We generated a humanized monoclonal antibody which blocks ERp72 enzyme activity (anti-ERp72). Anti-ERp72 inhibits platelet functional responses and thrombosis., Summary: Background Within the endoplasmic reticulum, thiol isomerase enzymes modulate the formation and rearrangement of disulfide bonds in newly folded proteins entering the secretory pathway to ensure correct protein folding. In addition to their intracellular importance, thiol isomerases have been recently identified to be present on the surface of a number of cell types where they are important for cell function. Several thiol isomerases are known to be present on the resting platelet surface, including PDI, ERp5 and ERp57, and levels are increased following platelet activation. Inhibition of the catalytic activity of these enzymes results in diminished platelet function and thrombosis. Aim We previously determined that ERp72 is present at the resting platelet surface and levels increase upon platelet activation; however, its functional role on the cell surface was unclear. We aimed to investigate the role of ERp72 in platelet function and its role in thrombosis. Methods Using HuCAL technology, fully humanized Fc-null anti-ERp72 antibodies were generated. Eleven antibodies were screened for their ability to inhibit ERp72 activity and the most potent inhibitory antibody (anti-ERp72) selected for further testing in platelet functional assays. Results and conclusions Anti-ERp72 inhibited platelet aggregation, granule secretion, calcium mobilisation and integrin activation, revealing an important role for extracellular ERp72 in the regulation of platelet activation. Consistent with this, infusion of anti-ERp72 into mice protected against thrombosis., (© 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbβ3. PPARγ agonists disrupt the interaction of Gα13 with integrin β3. This is attributed to an upregulation of protein kinase A activity., Summary: Background Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. Objectives Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signaling. Both GPVI and GPCR signaling pathways lead to αIIbβ3 activation, and signaling through αIIbβ3 plays a critical role in platelet function and normal hemostasis. Methods The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signaling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signaling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by Western blotting. Results Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signaling, including the integrin β3 subunit, Syk, PLCγ2, focal adhesion kinase (FAK) and Akt, was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was because of an increase in PKA activity following treatment with PPARγ receptor agonists. Conclusions This study provides further evidence for antiplatelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signaling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation., (© 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

The influence of lead (10 mg/kg) and ethanol (10% v/v, in drinking water) administration, either alone or in combination for 8 weeks was investigated on the uptake of lead in tissues, dopamine, benzodiazepine and cholinergic (muscarinic) receptors, motor activity, number of fighting episodes and several selected lead-sensitive biochemical indices in young rats. Lead or ethanol treatment did not elicit any appreciable influence on body weight gain, tissue weight, and food intake. However, a decreased amount of mean water intake was noticed in animals ingesting ethanol plus lead. Both lead and ethanol when administered individually exacerbate the decrease of blood delta-aminolevulinic acid dehydratase (ALAD) activity while lead and ethanol administered together exhibited a pronounced inhibition of ALAD activity. A significant increase in hepatic GSH levels, hepatic and brain MDA levels was also observed in animals co-exposed to lead and ethanol compared to lead alone treated rats. Simultaneous exposure to lead and ethanol also resulted in a significantly more pronounced decrease in binding of [3H]fluintrazepam in membranes prepared from the fronto-cortical region compared to the corresponding controls. The binding of [3H]spiroperidol to striatal and [3H]quinuclidinyl benzylate (QNB) to cerebellar membranes remained unaltered in all the exposed animals. Spontaneous locomotor activity and aggressive behaviour increased significantly in the group treated with both lead and ethanol compared to the control group. The lead concentrations in blood, liver, kidney and brain were significantly higher in rats exposed simultaneously to lead and ethanol compared to lead alone exposed group. The results indicate more pronounced neurotoxic and neurobehavioural changes in animals co-exposed to lead and ethanol; however, the exact mechanism or site of its action is still not clear.

We describe the clinical features of 11 patients with human immunodeficiency virus infection in whom tuberculosis was undiagnosed and untreated prior to death. Most patients (9 of 11) had pulmonary complaints and 8 of 11 had roentgenographic findings suggestive of tuberculosis (hilar or mediastinal adenopathy, pleural effusion, apical infiltrate or miliary pattern). Despite these findings, tuberculin skin tests were not performed in any of the patients. Acid-fast smears of sputum were obtained in three cases and bronchoscopy performed in only four, reflecting the low index of suspicion for tuberculosis. Pneumocystis carinii pneumonia was the presumptive diagnosis in nine cases but was confirmed in only one case. Autopsy revealed tuberculosis as the cause of death in four patients. Of the seven patients who did not undergo autopsy, disseminated tuberculosis, manifest by mycobacteremia, was the only life-threatening illness identified and probably contributed to death. Increased awareness of the clinical and roentgenographic features of tuberculosis in HIV-infected patients, combined with more intensive use of acid-fast smears and tuberculin skin testing, are necessary in order to decrease mortality from this treatable complication of HIV-infection.

Clinical and diagnostic data were collected from 22 men with iliac artery aneurysms treated surgically over a period of 22 years. Their ages ranged from 47 to 80 years (mean 64.0). Eight patients had multiple aneurysms. Thirty isolated iliac artery aneurysms were detected, 20 aneurysms (66.6%) located on the right and 10 (33.3%) on the left side. Twenty-six aneurysms were found in the common iliac artery (86.6%). Fifteen patients were symptomatic (68.2%); rupture occurred in five patients (22.7%), three of whom were initially asymptomatic. Thirteen of 17 patients whose aneurysms did not rupture had a palpable mass (76.4%), and three had bruits in the area of the aneurysm. All 22 patients were subjected to operative procedures. Seventeen patients operated upon electively survived, whereas only three patients who were operated upon after rupture survived. Graft interposition was the most common procedure. All 20 patients who survived after the operation were followed. Two died of myocardial infarction three and five years later, one of cancer six years later, and one of an unknown cause eight years after operation. Iliac artery aneurysms are extremely rare; their diagnosis is very difficult. The mortality rate is two times higher than in aortic aneurysms, once the diagnosis has been established. Therefore elective resection and arterial reconstruction are recommended.