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Πέμπτη 7 Απριλίου 2022

Guiding Principles for Surgical Pathways: A Tool for Improving Outcomes and Patient Safety

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Surgical activity is an important aspect for the management of health and safety processes and from an organizational perspective is one of the most complex activities performed in hospitals. It is often a defining and high value feature for any healthcare facility while being one of the most high-risk procedures for patients with the highest number of avoidable adverse events. To ensure effective management of surgical pathways, they need to be considered from the perspective of clinical governance which ta kes a global approach to planning and management with the goal of improving safety and quality for patients. This paper contains the main features of this objective outlined within the document issued subsequent to the State-Regional Italian Government conference. This regulatory effort includes effective recommendations to make surgical pathways safer and more efficient with particular reference to lean management, patient blood management and patient safety.

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Effect of acute aerobic exercise before immunotherapy and chemotherapy infusion in patients with metastatic non-small-cell lung cancer: protocol for the ERICA feasibility trial

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Introduction

Patients with metastatic non-small cell lung cancer (mNSCLC) suffer from numerous symptoms linked to disease and treatment which may further impair the patient's overall condition. In addition to its benefits on quality of life and fatigue, physical exercise may improve treatment response, notably due to its known effects on the immune system. The ERICA study is designed to assess the feasibility of a supervised acute physical exercise therapy realised immediately prior immune-chemotherapy infusion in patients with mNSCLC. Secondary objectives will examine the effects of acute exercise combined with an unsupervised home-walking programme on clinical, physical, psychosocial and biological parameters.

Methods and analysis

ERICA is a prospective, monocentric, randomised controlled, open-label feasibility study conducted at the Centre Léon Bérard Comprehensive Cancer Center (France). Thirty patients newly diagnosed with mNSCLC will be randomised (2:1 ratio) to the 'exercise' or the 'control' group. At baseline and during the last treatment cycle, participants in both groups will receive Physical Activity recommendations, and two nutritional assessments. In the exercise group, participants will receive a 3-month programme consisting of a supervised acute physical exercise session prior to immune-chemotherapy infusion, and an unsupervised home-based walking programme with an activity tracker. The acute exercise consists of 35 min interval training at submaximal intensity scheduled to terminate 15 min prior to infusion. Clinical, physical, biological and psychosocial parameters will be assessed at baseline, 3 and 6 months after inclusion. Biological measures will include immune, inflammatory, metabolic, oxidative stress biomarkers and molecular profiling.

Ethics and dissemination

The study protocol was approved by the French ethics committee (Comité de protection des personnes Ile de France II, N°ID-RCB 20.09.04.65226, 8 December 2020). The study is registered on ClinicalTrials.gov (NCT number:NCT04676009) and is at the pre-results stage. All participants will sign an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences.

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Patient-reported experiences and views on the Cytosponge test: a mixed-methods analysis from the BEST3 trial

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Objectives

The BEST3 trial demonstrated the efficacy and safety of the Cytosponge-trefoil factor 3, a cell collection device coupled with the biomarker trefoil factor 3, as a tool for detecting Barrett's oesophagus, a precursor of oesophageal adenocarcinoma (OAC), in primary care. In this nested study, our aim was to understand patient experiences.

Design

Mixed-methods using questionnaires (including Inventory to Assess Patient Satisfaction, Spielberger State-Trait Anxiety Inventory-6 and two-item perceived risk) and interviews.

Outcome measures

Participant satisfaction, anxiety and perceived risk of developing OAC.

Setting

General practices in England.

Participants

Patients with acid reflux enrolled in the intervention arm of the BEST3 trial and attending the Cytosponge appointment (N=1750).

Results

1488 patients successfully swallowing the Cytosponge completed the follow-up questionnaires, while 30 were interviewed, including some with an unsuccessful swallow.

Overall, participants were satisfied with the Cytosponge test. Several items showed positive ratings, in particular convenience and accessibility, staff's interpersonal skills and perceived technical competence. The most discomfort was reported during the Cytosponge removal, with more than 60% of participants experiencing gagging. Nevertheless, about 80% were willing to have the procedure again or to recommend it to friends; this was true even for participants experiencing discomfort, as confirmed in the interviews.

Median anxiety scores were below the predefined level of clinically significant anxiety and slightly decreased between baseline and follow-up (p < 0.001). Interviews revealed concerns around the ability to swallow, participating in a clinical trial, and waiting for test results.

The perceived risk of OAC increased following the Cytosponge appointment (p<0.001). Moreover, interviews suggested that some participants had trouble conceptualising risk and did not understand the relationships between test results, gastro-oesophageal reflux and risk of Barrett's oesophagus and OAC.

Conclusions

When delivered during a trial in primary care, the Cytosponge is well accepted and causes little anxiety.

Trial registration number

ISRCTN68382401.

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Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis

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Objective

To quantify sex differences in activity and severity of multiple sclerosis (MS) and how it depends on disease duration and time since clinical onset.

Methods

All Danish citizens with onset of relapsing MS since 1996 who have received disease-modifying therapy have been followed with annual or biannual control visits with mandatory notification of the Danish Multiple Sclerosis Registry. Men and women were compared by the inverse probability of being female. Relapse rates and changes in the Expand ed Disability Status Scale (EDSS) scores were analysed with weighted general linear models, and we used weighted Cox regression for HRs between men and women for different EDSS endpoints.

Results

We included 3028 men and 6619 women. The weighted female:male relapse rate ratio was 1.16 (95% CI: 1.10 to 1.22) but after age 50 years, the difference disappeared. The annualised increase in EDSS was 0.07 in men (95% CI: 0.05 to 0.08) and 0.05 in women (95% CI: 0.04 to 0.06); p=0.017. With women as reference, the HR for reaching EDSS 4 was 1.34 (95% CI: 1.23 to 1.45; p<0.001), and for reaching EDSS 6 it was 1.43 (95% CI: 1.28 to 1.61; p<0.001). The diagnostic delay did not differ significantly between the sexes.

Conclusion

Women have more inflammatory disease activity in terms of relapses than men up to the age of menopause indicating that sex hormones may play a role. Men are more subject to the neurodegenerative component of MS than women, particularly after the age of 45 years.

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Gait Phase Subdivision and Leg Stiffness Estimation During Stair Climbing

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Leg stiffness is considered a prevalent parameter used in data analysis of leg locomotion during different gaits, such as walking, running, and hopping. Quantification of the change in support leg stiffness during stair ascent and descent will enhance our understanding of complex stair climbing gait dynamics. The purpose of this study is to investigate a methodology to estimate leg stiffness during stair climbing and subdivide the stair climbing gait cycle. Leg stiffness was determined as the ratio of changes in ground reac tion force in the direction of the support leg ${F}_{l}$ (leg force) to the respective changes in length ${L}_{l}$ during the entire stance phase. Eight subjects ascended and descended an instrumented staircase at different cadences. In this study, the changes of leg force and length (force–length curve) are described as the leg stiffness curve, the slope of which represents the normalized stiffness during stair climbing. The stair ascent and descent gait cycles were subdivided based on the negative and positive work fluctuations of the center-of-mass (CoM) work rate curve and the characteristics of leg stiffness. We found that the leg stiffness curve consists of several segments in which the force–length relationship was similarly linear and the stiffness value was relatively constant; the phase divided by the leg stiffness curve corresponds to the phase divided by the CoM work rate curve. The results of this study may guide biomimetic control strategies for a wearable lowe r-extremity robot for the entire stance phase during stair climbing.
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Effects of Low Protein-High Carbohydrate Diet during Early and Late Pregnancy on Respiratory Quotient and Visceral Adiposity

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Background. Low Protein-High Carbohydrate (LPHC) diet during pregnancy is considered a nutritional and health problem related to the development of maternal metabolic alterations, such as fatty liver and obesity in the perinatal and postnatal period. It is known that increase in visceral adiposity tissue (VAT) modulates maternal metabolic rate, with the respiratory quotient (RQ) being a parameter related to that variable; however, it is unknown whether LPHC intake during pregnancy affects the VAT and the RQ. In this study, we examine if consumption of LPHC during pregnancy modifies the VAT and RQ in early and late periods of pregnancy. Methods. This is a longitudinal and cross-sectional study with Wistar rats during gestation (G) (3, 8, 15, and 20) and nonpregnant rats. Rats were fed with a co ntrol diet with 63/18% carbohydrate/protein and an experimental diet with 79/6% carbohydrate/protein. We studied water and food consumption and metabolic parameters such as RQ and energy expenditure (EE), calculated by indirect calorimetry. In the cross-sectional study, we determined visceral fat, as well as the concentration of free fatty acids, insulin, glucose, and lipid profile in serum. Results. Nonpregnant rats with LPHC intake decreased significantly in VAT (86%) and the RQ (18%); in pregnant rats in early (8G) and late pregnancy (15G) in LPHC diet, both parameters (VAT and RQ) (25%-92%) increased during light time. When comparing time points during pregnancy in the control and LPHC groups, the RQ increased in 15G during daytime compared to 8G during the night period (17 and 5%, respectively). In late pregnancy, LPHC intake and triacylglyceride levels increased and cholesterol and glucose decreased (45 and 26%, respectively), in comparison to nonpregnant rats. Conclusions. LP HC intake in nonpregnant rats decreases the RQ and VAT. Interestingly, the opposite occurs in early pregnancy: the RQ and VAT increased, and this correlates with free fatty acid (FFA) levels. The increase in RQ and VAT during light time in early pregnancy increased mobilization of carbohydrate and protein metabolism. These results suggest that LPHC intake during pregnancy increases the glucose metabolism as a compensatory mechanism for energy needs in the fetus and the mother in early pregnancy.
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Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway

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With unknown etiology and limited treatment options, neonatal hypoxic-ischemic brain damage (HIBD) remains a major cause of mortality in newborns. Ferroptosis, a recently discovered type of cell death triggered by lipid peroxidation, is closely associated with HIBD. High-mobility group box 1 (HMGB1), a molecule associated with inflammation damage, can induce neuronal death in HIBD. However, it remains unknown whether HMGB1 contributes to neuronal ferroptosis in patients with HIBD. Herein, glycyrrhizin (GL), an HMGB1 inhibitor, was used to investigate the relationship between ferroptosis and HMGB1. RAS-selective lethal 3(RSL3), a ferroptosis agonist, was administered to further confirm the changes in the signaling pathway between HMGB1 and ferroptosis. Western blot analysis revealed that GL mar kedly suppressed the expression of HMGB1 and increased the level of GPX4 in the context of HIBD. We observed changes in neuronal ultrastructure via transmission electron microscopy to further confirm the occurrence of ferroptosis. Real-time PCR indicated that GL inhibited the expression of ferroptosis-related genes and inflammatory factors. Immunofluorescence and immunohistochemistry staining confirmed GL inhibition of neuronal damage and ferroptosis in HIBD associated with GPX4 and ROS. GL not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by HIBD in vivo. More importantly, GL may improve oxidative stress imbalance and mitochondrial damage, alleviate the downstream production of inflammatory factors, and ultimately reduce ferroptosis and damage to cortical neurons following HIBD via the HMGB1/GPX4 pathway. In conclusion, we showed for the first time that GL could suppress the occurrence of neuronal ferroptos is and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway. These findings highlight the potential of HMGB1 signaling antagonists to treat neuronal damage by suppressing ferroptosis, provide new and unique insights into GL as a neuroprotective agent, and suggest new prevention and treatment strategies for HIBD.
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Optimized Protocol for the Isolation of Extracellular Vesicles from the Parasitic Worm Schistosoma mansoni with Improved Purity, Concentration, and Yield

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In the past decade, the interest in helminth-derived extracellular vesicles (EVs) increased owing to their role in pathogen-host communication. However, the availability of EVs from these parasitic worms is often limited due to the restricted occurrence and culturing possibilities of these organisms. Schistosoma mansoni is one of several helminths that have been shown to release EVs affecting the immune response of their host. Further investigation of mechanisms underlying these EV-induced effects warrants separation of EVs from other components of the helminth excretory/secretory products. However, isolation of high-purity EVs often come to the expense of reduced EV yield. We therefore aimed to develop an optimized protocol for isolation of EVs from S. mansoni schistosomula and adult worms with respect to purity, concentration, and yield. We tested the use of small (1.7 ml) iodixanol density gradients and demonstrated that this enabled western blot-based analysis of the EV marker protein tetraspanin-2 (TSP-2) in gradient fractions without additional concentration steps. Moreover, the concentration and yield of EVs obtained with small iodixanol gradients were higher compared to medium-sized (4.3 ml) or conventional large-sized (12 ml) gradients. Additionally, we provide evidence that iodixanol is preferred over sucrose as medium for the small density gradients, because EVs in iodixanol gradients reached equilibrium much faster (2 hours) and iodixanol but not sucrose was suitable for purification of schistosomula EVs. Finally, we demonstrate that the small iodixanol gradients were able to separate adult worm EVs from non-EV contaminants such as the blood digestion product hemozoin. Our optimized small iodixanol density gradient allows to simultaneously separate and con centrate EVs while reducing handling time and EV loss and can be applied for EVs from helminths and other limited EV sources.
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