Guanylate-binding protein 1 acts as a pro-viral factor for the life cycle of hepatitis C virus.

Viral infections trigger the expression of interferons (IFNs) and interferon stimulated genes (ISGs), which are crucial to modulate an antiviral response. The human guanylate binding protein 1 (GBP1) is an ISG and exhibits antiviral activity against several viruses. In a previous study, GBP1 was described to impair replication of the hepatitis C virus (HCV). However, the impact of GBP1 on the HCV life cycle is still enigmatic. To monitor the expression and subcellular distribution of GBP1 and HCV we performed qPCR, Western blot, CLSM and STED microscopy, virus titration and reporter gene assays. In contrast to previous reports, we observed that HCV induces the expression of GBP1. Further, to induce GBP1 expression, the cells were stimulated with IFNγ. GBP1 modulation was achieved either by overexpression of GBP1-Wt or by siRNA-mediated knockdown. Silencing of GBP1 impaired the release of viral particles and resulted in intracellular HCV core accumulation, while overexpression of GBP1 favored viral replication and release. CLSM and STED analyses revealed a vesicular distribution of GBP1 in the perinuclear region. Here, it colocalizes with HCV core around lipid droplets, where it acts as assembly platform and thereby favors HCV morphogenesis and release. Collectively, our results identify an unprecedented function of GBP1 as a pro-viral factor. As such, it is essential for viral assembly and release acting through tethering factors involved in HCV morphogenesis onto the surface of lipid droplets.

Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators?

BACKGROUND: Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. AIMS: To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. METHODS: A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. RESULTS: Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. CONCLUSION: The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes.

"Listen to Your Immune System When It's Calling for You": Monitoring Autoimmune Diseases Using the iShU App.

The immune system plays a key role in protecting living beings against bacteria, viruses, and fungi, among other pathogens, which may be harmful and represent a threat to our own health. However, for reasons that are not fully understood, in some people this protective mechanism accidentally attacks the organs and tissues, thus causing inflammation and leads to the development of autoimmune diseases. Remote monitoring of human health involves the use of sensor network technology as a means of capturing patient data, and wearable devices, such as smartwatches, have lately been considered good collectors of biofeedback data, owing to their easy connectivity with a mHealth system. Moreover, the use of gamification may encourage the frequent usage of such devices and behavior changes to improve self-care for autoimmune diseases. This study reports on the use of wearable sensors for inflammation surveillance and autoimmune disease management based on a literature search and evaluation of an app prototype with fifteen stakeholders, in which eight participants were diagnosed with autoimmune or inflammatory diseases and four were healthcare professionals. Of these, six were experts in human-computer interaction to assess critical aspects of user experience. The developed prototype allows the monitoring of autoimmune diseases in pre-, during-, and post-inflammatory crises, meeting the personal needs of people with this health condition. The findings suggest that the proposed prototype-iShU-achieves its purpose and the overall experience may serve as a foundation for designing inflammation surveillance and autoimmune disease management monitoring solutions.

Cycling through 360° Virtual Reality Tourism for Senior Citizens: Empirical Analysis of an Assistive Technology.

In recent years, there has been a renewed interest in using virtual reality (VR) to (re)create different scenarios and environments with interactive and immersive experiences. Although VR has been popular in the tourism sector to reconfigure tourists' relationships with places and overcome mobility restrictions, its usage in senior cyclotourism has been understudied. VR is suggested to positively impact tourism promotion, cycling simulation, and active and healthy ageing due to physical and mental rehabilitation. The purpose of this study is to assess the senior citizens' perceived experience and attitudes toward a designed 360° VR cyclotouristic experiment, using a head-mounted display (HMD) setting within a laboratory context. A total of 76 participants aged between 50 and 97 years old were involved in convergent parallel mixed-method research, and data were collected using a questionnaire based on the technology acceptance model, as well as the researchers' field notes. Findings suggest that 360° VR with HMD can be an effective assistive technology to foster senior cyclotourism by promoting tourism sites, simulating the cycling pedaling effect, and improving senior citizens' general wellbeing and independence with physical and mental rehabilitation.

A dynamic web-based decision aid to improve informed choice in organised breast cancer screening. A pragmatic randomised trial in Italy.

BACKGROUND: Improving the quality of information and communication is a priority in organised breast cancer screening and an ethical duty. Programmes must offer the information each woman is looking for, promoting informed decision-making. This study aimed to develop and evaluate a web-based dynamic decision aid (DA). METHODS: A pragmatic randomised trial carried out in six regional organised screening programmes recruited women at the first invitation receiving DA or a web-based standard brochure (SB). The primary outcome was informed choice measured on knowledge, attitudes, and intentions. Follow-up period: 7-10 days. Secondary outcomes included participation rate, satisfaction, decisional conflict, and acceptability of DA. RESULTS: Two thousand one hundred and nineteen women were randomised and 1001 completed the study. Respectively, 43.9% and 36.9% in the DA and SB reached the informed choice. The DA gave a 13-point higher proportion of women aware about overdiagnosis compared to SB (38.3% versus 25.2%, p < 0.0001). The percentage of women attending screening was the same: 84% versus 83%. Decisional conflict was significantly lower in the DA group (14.4%) than in the SB group (19.3%). CONCLUSION: DA increases informed choice. Complete information including the pros, cons, controversies, and overdiagnosis-overtreatment issues boost a woman's knowledge without reducing the rate of actual screening participation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT03097653.

Epigenetic asymmetry of imprinted genes in plant gametes.

Plant imprinted genes show parent-of-origin expression in seed endosperm, but little is known about the nature of parental imprints in gametes before fertilization. We show here that single differentially methylated regions (DMRs) correlate with allele-specific expression of two maternally expressed genes in the seed and that one DMR is differentially methylated between gametes. Thus, plants seem to have developed similar strategies as mammals to epigenetically mark imprinted genes.

Photodynamic inactivation of multidrug-resistant bacteria in hospital wastewaters: influence of residual antibiotics.

One environmental concern related to hospital effluents is discharge of them without preliminary treatment. Antimicrobial photodynamic inactivation (PDI) may represent an alternative to the traditional expensive, unsafe and not always effective disinfection methods. The main goal of this work was to assess the efficiency of PDI on clinical multidrug-resistant (MDR) bacteria in hospital wastewaters in order to evaluate its potential use in treating hospital effluents. The efficiency of PDI was assessed using a cationic porphyrin as the photosensitizer (PS), four MDR bacteria either in phosphate buffered saline or in filtrated hospital wastewaters. The synergistic effect of PDI and antibiotics (ampicillin and chloramphenicol) was also evaluated, as well as the effect of the surfactant sodium dodecyl sulfate (SDS). The results show the efficient inactivation of MDR bacteria in PBS (reduction of 6-8 log after 270 min of irradiation at 40 W m(-2) with 5.0 µM of PS). In wastewater, the inactivation of the four MDR bacteria was again efficient and the decrease in bacterial survival starts even sooner. A faster decrease in bacterial survival occurred when PDI was combined with the addition of antibiotics, at sub-inhibitory and inhibitory concentrations, but the SDS did not affect the PDI efficiency. It can be concluded that PDI has potential to be an effective alternative for the inactivation of MDR bacteria in hospital wastewaters and that the presence of antibiotics may enhance its effectiveness.

Pneumococcal Septic Shock Syndrome: A Deadly Condition Despite Vaccination.

Invasive pneumococcal disease is a serious infection with an elevated case-fatality rate that can be even higher among patients with asplenia. Its impact has been blunted by the widespread use of vaccines; even recently, in 2021, two new pneumococcal conjugate vaccines emerged. The authors present a case of a 58-year-old male, splenectomised with the immunisation schedule complete, who died of invasive pneumococcal disease with a fulminant course. It is highlighted that fever in a patient with impaired splenic function is an emergency, and despite the success of immunisation in reducing pneumococcal carriage and invasive disease, serotypes continue to change. Also, the local epidemiology may help guide situations where the immunisation recommendations are dubious regarding the implementation of the new vaccines.

Rigid Esophagoscopy for Foreign Body Extraction: Results and Complications in the Endoscopic Era.

Introduction Rigid esophagoscopy (RE) has long been a part of otolaryngology practice. In the past decades, the procedure was less commonly performed due to the advances and availability of flexible endoscopic techniques. This study aims to describe the outcomes of RE performed to treat foreign body ingestion and to evaluate risk factors associated with postoperative complications. Methods Patients who underwent RE to treat foreign body ingestion in an otolaryngology emergency department of a Portuguese tertiary university hospital, between 2010 and 2020, were included. A total of 162 cases were analyzed, and data was collected retrospectively. Results The most common foreign bodies were meat bone (31.5%, n = 47), food impaction (28.8%, n = 43), and fish bone (19.5%, n = 29). The proximal esophagus was by far the most frequent location (80%, n = 118). Esophageal perforation occurred in 8% (13 patients), and there was a 2.5% (n = 4) mortality rate. The odds ratio of an esophageal perforation if the foreign body was completely or partially located outside the proximal esophagus was 4.67 times that of a foreign body exclusively in the proximal esophagus (OR = 4.67 [95% CI: 1.39-15.72]; p = 0.016; Fisher's exact test). Conclusion RE remains an effective and important technique in the management of ingested foreign bodies, particularly if endoscopic removal is unsuccessful. Foreign body location outside the proximal esophagus was associated with esophageal perforation.

Correlation between Periodontitis and Gastritis Induced by Helicobacter pylori: A Comprehensive Review.

The goal of this comprehensive review was to verify if the prevalence of Helicobacter pylori (Hp) bacteria in patients with dyspepsia is higher in the oral cavity of periodontal or non-periodontal patients. The bibliographic search was conducted on scientific studies published in PubMed, Cochrane Library, SciELO, and BVS. The focus question was: "In patients with dyspepsia and periodontitis, is the prevalence of Hp bacteria in the oral cavity higher than in patients with only dyspepsia or without any disease?" The inclusion criteria were human studies in English, Portuguese, or Spanish languages, published between 2000 and 2022, that included patients over the age of 18 and aimed to evaluate the presence of Hp bacteria in the oral cavity and in the protective mucosal layer of the gastric lining of patients with the diseases (periodontitis and dyspepsia) or without disease; clinical trials, randomized controlled clinical trials, comparative studies, case-control studies, cross-sectional studies, and cohort studies. The methodological quality evaluation of the included articles was performed using the Joanna Briggs Institute tools. The final scores could be of "Low" quality (at least two "no" [red] or ≥ five "unclear" found), "Moderate" quality (one "no" [red] was found or up to four "unclear" criteria were met), or "High" quality (all green [yes] or at maximum two "unclear"). Of 155 potentially eligible articles, 10 were included in this comprehensive review after the application of the eligibility criteria. The selected studies were scrutinized regarding the relationship between Hp colonization in the oral cavity and stomach, its impact on severity and complications of gastric infection, as well as the effect of the presence of oral and gastric Hp on dental and systemic parameters. Hp can colonize periodontal pockets regardless of its presence in the stomach. There was a higher prevalence of oral biofilm in dyspeptic patients with periodontal disease, and worse control of bleeding and low oral hygiene was observed in periodontal compared to non-periodontal patients. For que quality assessment, the scientific studies included presented low to moderate methodological quality. Conclusions: It is possible to conclude that Hp is a bacterium that can colonize dental plaque independently of the stomach and vice versa; however, when both diseases are found, its presence may be more significant. Supra and subgingival dental plaque may be a reservoir of Hp, suggesting that patients with gastric infections are more likely to have Hp in the oral cavity. The results must be carefully analyzed due to the limitations present in this review.

Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.

Comprehensive characterization of protein modifications using mass spectrometry and dry blood spots.

PURPOSE: The main objective of this study is to characterize and analyze modified peptides in DBS samples. This includes deciphering their specific PTMs and understanding their potential impact on the population or disease cohort under study. EXPERIMENTAL DESIGN: Using mass spectrometry-based proteomic approaches, we performed a comprehensive analysis of DBS samples. Our focus was on the identification and quantification of modified peptides. We also took advantage of recent advances in DBS mass spectrometry to ensure accurate detection and quantification. RESULTS: A comprehensive analysis identified 972 modified peptides in DBS samples. Of these, a subset of 211 peptides was consistently present in all samples, highlighting their potential biological importance and relevance. This indicates a diverse spectrum of PTMs in the proteome of DBS samples. CONCLUSIONS AND CLINICAL RELEVANCE: Integration of mass spectrometry and proteomics has revealed a broad spectrum of modified peptides in DBS samples and highlighted their importance in biological processes and disease progression. Accurate detection of these PTMs may be critical for risk stratification and disease management. This study improves the understanding of molecular mechanisms underlying biological processes and disease development, providing important insights for clinical applications.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Association Between Knee Extension Strength and Functional Capacity After Intensive Care Unit Discharge: A 6-Mo Prospective Cohort Study.

INTRODUCTION: Assessing functional improvement after intensive care unit discharge is particularly challenging. The aim of this study was to measure the association between (1) changes in knee extension muscle strength or quadriceps femoris and rectus femoris muscle thickness and (2) changes in functionality/function-related measurements in post-intensive care unit patients. METHODS: This prospective cohort study included adult patients without previous disability, consecutively selected after intensive care unit discharge. Some parameters, such as Short-Form 36, 6-min walking test, 1-min sit-to-stand, and Short Physical Performance Battery, were measured at baseline and 3 and 6 mos after discharge. Correlations were assessed and regression models were built to assess the association between evolution in knee extension strength or muscle thickness and evolution in functional tests. RESULTS: Thirty patients completed the follow-up. Moderate correlation was found between knee extension strength change and Short-Form 36 physical functioning (correlation coefficient [ ρ ] = 0.53), 6-min walking test ( ρ = 0.38), 1-min sit-to-stand ( ρ = 0.52), and Short Physical Performance Battery ( ρ = 0.38). Baseline values and changes in knee extension strength moderately predicted evolution in Short-Form 36 physical functioning ( r2 = 0.32, P = 0.006). Changes in muscle thickness were overall not associated with changes in functional variables. CONCLUSION: Changes in knee extension muscle strength may inform on functional progression over time after intensive care unit discharge, although confirmatory studies are needed.

Family Satisfaction With Critical Care: Before and After the COVID-19 Outbreak.

Introduction Family satisfaction with intensive care units (ICU) is recognized as a key component of the quality of care. As a result, family members are now more involved in the care process, and their needs are recognized throughout the ICU stay. The coronavirus disease 2019 (COVID-19) changed healthcare worldwide, due to the several restrictions imposed; the communication patterns changed drastically, and institutions were forced to adapt to create a balance between security and the needs of relatives. The aim of this study was to assess family members' satisfaction with the ICU and determine if the COVID-19 restructuring affected family satisfaction. Methods A prospective observational study was performed among the designated family members (DFM) of ICU patients over two time periods, a pre-pandemic period from December 2019 to February 2020 and a pandemic period from May 2020 to February 2021. The Family Satisfaction in the Intensive Care Unit 24 (FS-ICU 24) questionnaire, which was given to the DFM, was the instrument used to determine family satisfaction. Results The study involved 290 DFM, 175 during the pre-pandemic phase and 115 during the pandemic period. The overall and domain-specific family satisfaction scores were high (score > 80) in both the pre-pandemic and pandemic periods. The greatest satisfaction levels were related with symptom management and how nurses and doctors cared for the patient. No statistical differences were found between the two time periods. Lastly, a positive association between the two domains explored by FS-ICU 24, satisfaction with care and satisfaction with decision-making process, was verified in both time frames. Conclusion The data obtained revealed very good outcomes on the different FS-ICU 24 domains, in line with other studies in literature. No significant differences were found between the pre-pandemic and pandemic periods, suggesting that the measures implemented during the COVID-19 were successful. The importance of involving families in the decision-making process, providing them with accurate information, and active listening, as well as using better communication skills, is emphasized throughout all these results. The relevance of measuring family satisfaction should be brought to the attention of family members and healthcare professionals so that additional research may be conducted.

Impact of an Antimicrobial Stewardship Strategy on Surgical Hospital Discharge: Improving Antibiotic Prescription in the Transition of Care.

Antimicrobial stewardship programs (AMSPs) are essential elements in reducing the unnecessary overprescription of antibiotics. Most of the actions of these programs have focused on actions during acute hospitalization. However, most prescriptions occur after hospital discharge, which represents a necessary and real opportunity for improvement in these programs. We present an AMSP multifaceted strategy implemented in a surgical department which was carried out by a multidisciplinary team to verify its reliability and effectiveness. Over a 1-year post-implementation period, compared to the pre-intervention period, a significant reduction of around 60% in antibiotic exposure occurred, with lower economic cost and greater safety.