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There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.

Environmental noise directive requires Member States to produce and periodically update strategic noise maps for agglomerates in order to evaluate citizens’ noise exposure before the action plan. Its ultimate purpose is to mitigate the highest or most harmful noise levels. Available tools do not provide a point-to-point indication of the predominant sources to be addressed by intervention on the sources by individual owners. Recently, noise source predominance maps were developed to show the predominant source at each point of the calculation grid of the strategic noise map by means of polygons and colors. Intensity noise source predominance maps were also developed to add the visualization of noise exposure levels by coloring the polygons according to a color scale. This work investigates their applicability in agglomerates and defines an additional indicator with the purpose of connecting the high levels of citizen exposure to its predominant source. The new approach provides an aid to administrations in identifying areas where singular noise mitigations would be truly effective in improving the citizen’s quality of life by ensuring a noticeable decrease in total noise while reducing exposure to the specific source.

Background Cardiac high-sensitivity troponin T (hs-cTnT) is linked to the cardioembolic origin, severity, and outcome of acute ischemic stroke. Furthermore, larger brain infarctions are often accompanied by impaired dynamic cerebral autoregulation (dCA), which is also indicative of a poor prognosis. Objectives This study aimed to investigate whether hs-cTnT levels can serve as a predictor of dCA impairment. Design Retrospective cohort study. Methods In 330 consecutive patients with stroke (age 71 years [IQR 59-78]; 100 women; 229 territorial and 111 non-territorial brain infarcts) with successful dCA assessment, hs-cTnT levels were measured within 24 hours of stroke onset. These measurements were analyzed in relation to cerebrovascular risk factors, stroke origin, stroke severity (National Institute of Health Stroke Scale, NIHSS at entry), modified Rankin scale (mRs) at 3 months, and stroke volume determined by cranial computed tomography perfusion (CTP). dCA was assessed using transfer function analysis, which assessed the relationship between middle cerebral artery blood flow velocity and blood pressure. Coherence, gain, and phase were estimated across 3 frequency ranges: very low (0.02-0.07 Hz), low (0.07-0.15 Hz), and high (0.15-0.5 Hz). Results In univariate analysis, hs-cTnT was associated with cardioembolism and territorial infarction. In the multinomial logistic regression analysis, independent risk factors for the presence of a territorial infarction included atrial fibrillation, the NIHSS score, the infarct core on CTP, cardioembolism, and large vessel disease, but not hs-cTnT levels. Risk factors for a poor outcome (mRs >2) included age, hs-cTnT, and NIHSS score. Overall, the coherence, gain, and phase were not predicted by hs-cTnT levels. Conclusions Hs-cTnT levels are associated with poor stroke outcomes. However, they do not predict dCA impairment. Registration ClinicalTrials.gov NCT04611672, 11.10.2020

Background: Artificial intelligence (AI) in medicine has primarily focused on diagnosing and treating diseases and assisting in the development of academic scholarly work. This study aimed to evaluate a new use of AI in orthopaedics: content generation for professional medical education. Quality, accuracy, and time were compared between content created by ChatGPT and orthopaedic surgery clinical fellows. Methods: ChatGPT and 3 orthopaedic adult reconstruction fellows were tasked with creating educational summaries of 5 total joint arthroplasty-related topics. Responses were evaluated across 5 domains by 4 blinded reviewers from different institutions who are all current or former total joint arthroplasty fellowship directors or national arthroplasty board review course directors. Results: ChatGPT created better orthopaedic content than fellows when mean aggregate scores for all 5 topics and domains were compared (P ≤ .001). The only domain in which fellows outperformed ChatGPT was the integration of key points and references (P = .006). ChatGPT outperformed the fellows in response time, averaging 16.6 seconds vs the fellows' 94 minutes per prompt (P = .002). Conclusions: With its efficient and accurate content generation, the current findings underscore ChatGPT's potential as an adjunctive tool to enhance orthopaedic arthroplasty graduate medical education. Future studies are warranted to explore AI's role further and optimize its utility in augmenting the educational development of arthroplasty trainees.

Older subjects usually show less of their upper incisors and more of their lower incisors than younger subjects.

Acoustic cameras (ACs) have become very popular in the last decade as an increasing number of applications in environmental acoustics are observed, which are mainly used to display the points of greatest noise emission of one or more sound sources. The results obtained are not yet certifiable because the beamforming algorithms or hardware behave differently under different measurement conditions, but at present, not enough studies have been dedicated to clarify the issues. The present study aims to provide a methodology to extract analytical features from sound maps obtained with ACs, which are generally only visual information. Based on the inputs obtained through a specific measurement campaign carried out with an AC and a known sound source in free field conditions, the present work elaborated a methodology for gathering the coordinates of the maximum emission point on screen, its distance from the real position of the source and the uncertainty associated with this position. The results obtained with the proposed method can be compared, thus acting as a basis for future comparison studies among calculations made with different beamforming algorithms or data gathered with different ACs in all real case scenarios. The method can be applicable to any other sector interested in gathering data from intensity maps not related to sound.

Targeted therapies have increased cancer therapy-related diarrhea (CTD) burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib is a pan-HER tyrosine kinase inhibitor approved for breast cancer treatment and causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal drug for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence /severity of neratinib-induced diarrhea without concomitant administration of loperamide in female beagle dogs. A pilot study using 3 dogs determined a maximum daily tolerated dose of neratinib was between 40 and 80 mg; this dose would induce a consistent incidence/severity of diarrhea without risking severe dehydration. In the definitive study, 24 female beagle dogs (8/group) received neratinib once daily and placebo capsules (CTR) four times/day, or neratinib once daily and crofelemer 125 mg delayed-release tablets given two times (BID), or neratinib once daily and crofelemer 125 mg delayed-release tablets given four times per day (QID). Fecal scores were collected twice daily using an established canine stool scoring scale called the Purina Fecal Scoring (PFS) System. After 28 days, using analysis of covariance (ANCOVA), dogs in the CTR group had a significantly higher average number of weekly loose/watery stools (PFS of 6 or 7) when compared to either crofelemer BID (8.71±2.2 vs. 5.96±2.2, p = 0.028) or crofelemer QID (8.70±2.2 vs. 5.74±2.2, p = 0.022) treatment groups. The average number of weekly loose/watery stools were not different between the crofelemer BID and QID treatment groups (p = 0.84). This study showed that crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the need for any loperamide administration.

The aim of this study was to ascertain whether dynamic cerebral autoregulation (CA) in the middle cerebral artery (MCA) is disturbed by cerebral infarctions outside the MCA territory.

Mechanical impedance (MI) defines the ability of a system to vibrate as a consequence of force application. In the recent years, the correlation of this parameter with tire-road noise and other characteristics has gained certain attention. Nevertheless, the information about this topic is still insufficient. Usually, the force is set through an impulse hammer as a master and the acceleration is measured through an accelerometer as a response in order to measure the corresponding Frequency Response Function (FRF). The objectives of the study presented in this paper are i) to analyse the differences between the axial mechanical impedance (complex ratio of force and velocity referred to the same point, named driving-point impedance) and the non-axial mechanical impedance (complex ratio of the force at the point i and velocity at the point j, named transfer impedance); ii) to analyse the effect of adding crumb rubber (2% by mixture weight) and of the percentage of bitumen on the mechanical impedance for the bituminous samples. Therefore, laboratory tests on asphalt concrete specimens have been performed, using an instrumentation system composed of i) an impact hammer reporting the impact force value; ii) an impedance head measuring the direct impact force and the direct acceleration at the hitting point location; iii) a piezoelectric accelerometer measuring the transfer acceleration at a certain distance from the hitting point location. Results demonstrate that the ratio between the repeatability and the average is quite constant, while for heights higher than 10 cm, also MI tends to be independent on the height. A number of recommendations have been made based on the results of the present research.

Clinicians often have to face infections caused by microorganisms that are difficult to eradicate due to their resistance and/or tolerance to antimicrobials. Among these pathogens, Pseudomonas aeruginosa causes chronic infections due to its ability to form biofilms on medical devices, skin wounds, ulcers and the lungs of patients with Cystic Fibrosis. In this scenario, the plant world represents an important reservoir of natural compounds with antimicrobial and/or antibiofilm properties. In this study, an extract from the leaves of Combretum micranthum G. Don, named Cm4-p, which was previously investigated for its antimicrobial activities, was assayed for its capacity to inhibit biofilm formation and/or to eradicate formed biofilms. The model strain P. aeruginosa PAO1 and its isogenic biofilm hyperproducer derivative B13 were treated with Cm4-p. Preliminary IR, UV-vis, NMR, and mass spectrometry analyses showed that the extract was mainly composed of catechins bearing different sugar moieties. The phytocomplex (3 g/L) inhibited the biofilm formation of both the PAO1 and B13 strains in a significant manner. In light of the obtained results, Cm4-p deserves deeper investigations of its potential in the antimicrobial field.

Objectives: Whether different antihypertensive drug classes in high blood pressure (HBP) pre-stroke treatment affect dynamic cerebral autoregulation (dCA), stroke severity, and outcome. Methods: Among 337 consecutive ischemic stroke patients (female 102; median age 71 years [interquartile range, [IQR 60; 78]; NIHSS median 3 [IQR 1; 6]) with assessment of dCA, 183 exhibited the diagnosis of HBP. dCA parameters’ gain and phase were determined by transfer function analysis of spontaneous oscillations of blood pressure and cerebral blood flow velocity. Results: Patients used beta-blockers (n = 76), calcium channel blockers (60), diuretics (77), angiotensin-converting enzyme inhibitors (59), or angiotensin-1 receptor blockers (79), mostly in various combinations of two or three drug classes. dCA parameters did not differ between the non-HBP and the different HBP medication groups. Multinomial ordinal logistic regression models revealed that the use of diuretics decreased the likelihood of a less severe stroke (odds ratio 0.691, 95% CI 0.493; 0.972; p = 0.01) and that beta-blockers decreased the likelihood of a better modified Rankin score at 3 months (odds ratio 0.981, 95% CI 0.970; 0.992; p = 0.009). Other independent factors associated with stroke outcome were penumbra and infarct volume, treatment with mechanical thrombectomy, and the initial National Institute of Health Stroke Scale score. Interpretation: In this cohort of ischemic minor to moderate stroke patients, pre-stroke antihypertensive treatment with diuretics was associated with a more severe neurological deficit on admission and pre-stroke treatment with beta-blockers with a poorer 3-month outcome. The antihypertensive drug class used pre-stroke did not impact dCA.

Background: In the Brazilian northeast region, the leaves of a plant scientifically known as Aristolochia cymbifera (A. cymbifera) are therapeutically used to treat different conditions, including fevers, ulcers and stomach disorders. Objective: To explore its effects in the oral cavity, this study aimed to evaluate the presence of morphological, cellular, and tissue modifications in the oral mucosa of rats treated with different A. cymbifera solutions. Materials and Methods: The rats were divided into 6 groups: Group 1 was treated with 0.3 ml of vehicle (DMSO and water); Group 2 treated with 0.3 ml of A. cymbifera-ethanolic extract 4mg/ml; Group 3 treated with 0.3 ml of A. cymbifera-hexane extract 4mg/ml; Group 4 treated with 0.3 ml of A. cymbifera-ethanolic extract 10mg/ml; Group 5 treated with 0.3 ml of A. cymbifera-hexane extract 10mg/ml; and Group 6 treated with 0.3 ml of chlorhexidine gluconate 0.12%. All groups were treated twice daily by applying the solutions into the oral cavity, over a total period of 24 days. To analyze cytotoxicity on cells, the micronucleus test was performed, and an additional histopathologic analysis was conducted in order to evaluate tissue changes such as inflammatory infiltration, desquamation, and degeneration of cells. Results: Results showed that the cytotoxicity of the A cymbifera -based solutions was similar to those of chlorhexidine, and all groups showed morphological characteristics of normal mucosa after treatments. Conclusion: It is concluded that no cytotoxicity was present after treatment with extracts of Aristolochia cymbifera, showing its potential for the development of future clinical trials.

Nodular regenerative hyperplasia (NRH) is a primary disease of the liver that may cause noncirrhotic portal hypertension. Common causes include autoimmune, hematologic, immune deficiency, and myeloproliferative disorders. Given the limited data regarding the development of NRH in contemporary immunosuppressive protocols and the occurrence of NRH post-liver transplantation, we systematically reviewed NRH as it pertains to liver transplantation. We performed a comprehensive search for NRH and transplantation. Nineteen studies were identified with relevant data for NRH as an indication for a liver transplant. Thirteen studies were identified with relevant data pertaining to NRH development after liver transplant. Pooled analysis revealed 0.9% of liver transplant recipients had NRH. A total of 113 patients identified with NRH underwent liver transplantation. Most series report transplants done after the failure of endoscopic banding and TIPS management of portal hypertension. Reported 5-year graft and patient survival ranged from 73%–78% and 73%–90%. The pooled incidence of NRH after liver transplant for all indications was 2.9% and caused complications of portal hypertension. Complications related to portal hypertension secondary to NRH are a rare indication for a liver transplant. NRH can develop at any time after liver transplantation often without an identifiable cause, which may lead to portal hypertension requiring treatment or even re-transplantation.

We investigated the mechanism underlying Chiari malformation type I (CM-I) and classified it according to the morphometric analyses of posterior cranial fossa (PCF) and craniocervical junction (CCJ). Three independent subtypes of CM-I were confirmed (CM-I types A, B, and C) for 484 cases and 150 normal volunteers by multiple analyses. CM-I type A had normal volume of PCF (VPCF) and occipital bone size. Type B had normal VPCF and small volume of the area surrounding the foramen magnum (VAFM) and occipital bone size. Type C had small VPCF, VAFM, and occipital bone size. Morphometric analyses during craniocervical traction test demonstrated instability of CCJ. Foramen magnum decompression (FMD) was performed in 302 cases. Expansive suboccipital cranioplasty (ESCP) was performed in 102 cases. Craniocervical posterolateral fixation (CCF) was performed for CCJ instability in 70 cases. Both ESCP and FMD showed a high improvement rate of neurological symptoms and signs (84.4%) and a high recovery rate of the Japanese Orthopaedic Association (JOA) score (58.5%). CCF also showed a high recovery rate of the JOA score (69.7%), with successful joint stabilization (84.3%). CM-I type A was associated with other mechanisms that caused ptosis of the brainstem and cerebellum (CCJ instability and traction and pressure dissociation between the intracranial cavity and spinal canal cavity), whereas CM-I types B and C demonstrated underdevelopment of the occipital bone. For CM-I types B and C, PCF decompression should be performed, whereas for small VPCF, ESCP should be performed. CCF for CCJ instability (including CM-I type A) was safe and effective.

Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. Methods We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). Results We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). Conclusions Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical–physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Environmental noise prevention starts from strategic noise maps of main transport infrastructures and agglomerations. Graduated colors are representative of the average noise levels produced in space by each individual source, or the by the overall sum. Among their purposes, communication of results to population has been the most neglected. The present paper proposes predominance maps for the first time in environmental acoustic (NSP). NSP are visualization tool showing the predominant source in each point by means of polygons and colors. Also Intensity Noise Source Predominance maps (I-NSP) are proposed, which add visualizations of noise exposure levels to NSP by coloring the polygons according to a color-scale. Both NSP and I-NSP are new visualization that would help understanding and assigning responsibilities for exceeding limits, but they also represent a valid support for locating the acoustic monitoring stations when required. As case studies, the maps are calculated in port areas, as they are large areas with a great variability of different types of noise sources and represent a smaller case than agglomeration, but with higher complexity.

BackgroundDigital therapeutics, an emerging type of medical approach, is defined as evidence-based therapeutic interventions through qualified software programs that help prevent, manage, or treat chronic diseases such as type 2 diabetes mellitus (T2DM), which has high social and economic burden. Klivo, a startup certified by the Brazilian Society of Diabetes, developed the first digital therapeutic product for managing T2DM in Brazil, reaching 21 of 24 states. Klivo has continuously been improving its model of behavior change on the basis of an intensive lifestyle intervention method that addresses individuals' needs-the Klivo Intervention Program for T2DM (KIPDM). To test the most recent version of the KIPDM, we will evaluate the ongoing management of daily life habits in patients with T2DM by measuring clinically significant outcomes. To improve the transparency of further results, here we will present the study protocol and detail the plan for the research project, including the study design and the analysis strategies.MethodsThe KIPDM will be sponsored by health plans and healthcare provider organizations and will be free for patients (adults aged ≥ 18 years and Expected outcomesKIPDM patients should present improved HbA1c and TIR along the intervention as compared to baseline values. Findings from this study will provide insights into the health improvement of T2DM and other cardiometabolic conditions such as hypertension, dyslipidemia, and obesity by using a digital therapeutic strategy. By analyzing the patient's health over time, this study will also contribute to understanding comorbidities associated with this chronic condition in the Brazilian population.