Search

Ortiz-Prado, Esteban, Juan Sebastian Izquierdo-Condoy, María G. Dávila-Rosero, Jorge Vásconez-González, Ana M. Diaz, Carla E. Moyano, Vanessa Arcos-Valle, Ginés Viscor, and Joshua H. West. Reduced violence-related burden and mortality at higher altitudes: examining the association between high altitude living and homicide rates in Ecuador. High Alt Med Biol. 25:295-307, 2024. Background: Homicides are a major public health concern and a leading cause of preventable deaths worldwide. The relationship between altitude and homicides remains unclear, and evidence of the possible effects of living at high altitudes on homicide rates is limited. This research aimed to investigate the mortality rates resulting from various types of aggression that culminated in homicides in Ecuador and to explore potential differences associated with altitude. Methods: An ecological analysis of homicide rates in Ecuador was conducted from 2001 to 2022. Homicide cases and the population at risk were categorized based on their place of residence according to two altitude classifications: a binary classification of low (<2,500 m) and high altitude (>2,500 m), and a detailed classification according to criteria by the International Society for Mountain Medicine, which includes low (<1,500 m), moderate (1,500-2,500 m), high (2,500-3,500 m), and very high altitude (3,500-5,500 m) categories. Both crude and directly age-sex standardized mortality rates were calculated for each altitude category. Results: We analyzed a total of 40,708 deaths attributed to aggressions (ICD-10 codes X85-Y09). The total homicide rate for men was 21.29 per 100,000 (95% confidence interval [CI]: 9.55-32.37), whereas for women, it was 2.46 per 100,000 (95% CI: 1.44-3.27). Average rates across the 22 analyzed years were higher at low altitudes (men: 13.2/100,000 and women: 1.33/100,000) as compared with high altitudes (men: 5.79/100,000 and women: 1.05/100,000). Notably, the male-to-female rate difference was more pronounced at low altitudes (898%) than at high altitudes (451%). Conclusions: Our study revealed a higher prevalence of homicides in certain provinces and significant disparities in mortality rates between men and women. Although we cannot establish a direct relationship between altitude and homicide rates, further research is needed to explore potential confounding factors and a better understanding of the underlying causes for these variations.

The need for the development of specific and robust methodologies to elucidate the intricate pathological mechanisms of neurodegenerative diseases and discover effective treatments for prevention and remediation is evident. Alzheimer's disease, in particular, has become more prevalent as the global population has aged. β-Secretase, the β-site amyloid precursor protein cleaving enzyme (BACE1), is the protease that produces the β-amyloid peptide, which is considered one of the driving factors of Alzheimer's disease and an important target for treatment development. However, an understanding of its activity, modulation, and regulation is far from complete. This is in large part due to the complex nature of following its activity. Beyond the common requirements for all biosensors (ease of preparation and use), BACE1 probes also demand both stability at acidic pH and membrane localization. To overcome these hurdles, we exploit the modular self-assembly provided by fluorescent quantum dot (QD) sensors. As compared to other fluorophores, QDs provide enhanced fluorescence brightness and photostability, and their large surface area enables functionalization with peptide substrates together with targeting elements that localize the sensor to the areas of maximal BACE1 activity, all achieved through His-tag self-assembly. In vitro , the sensor demonstrated stability under acidic conditions, and using high-throughput plate reader assays, we determined BACE1 activity in-line with literature values and enabled the obtainment of the inhibitor constant of verubecestat, a small molecule inhibitor. The sensor was also transitioned to cellular experiments, where it demonstrated sensitivity to BACE1 activity and its modulation upon inhibitor treatment in a neuroblastoma cell line.

Objective: The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers., Summary Background Data: RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve., Methods: Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared., Results: The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications., Conclusion: Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest. Conflict of interest: The authors declare that no conflict of interest exists. No grants and financial support were received for this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: COVID-19 vaccination has become a pivotal global strategy in managing the pandemic. Despite COVID-19 no longer being classified as a Public Health Emergency of International Concern, the virus continues affecting people worldwide. This study aimed to evaluate risk factors and vaccine effectiveness on COVID-19-related hospital admissions, intensive care unit (ICU) admission and mortality within the Andalusian population throughout the pandemic., Methods: From March 2020 to April 2022, 671,229 individuals, out of 9,283,485 with electronic health records in Andalusia, experienced SARS-CoV-2 infection and were included in the analysis. Data on demographics, medical history, vaccine administration, and hospitalization records were collected. Associations between medical history, COVID-19 vaccines, and COVID-19 outcomes were assessed., Results: Our study identified 48,196 hospital admissions, 5,057 ICU admissions, and 11,289 deaths linked to COVID-19. Age, male sex, and chronic diseases were identified as risk factors, while the COVID-19 vaccine demonstrated protective effects, although with reduced effectiveness during the omicron variant period. However, the risk for these outcomes increased over time after receiving the last vaccine dose, particularly after six months, especially among those aged 60 or older., Conclusion: The global health challenge of COVID-19 persists, marked by emerging variants with higher virulence and severity, particularly among the unvaccinated and those beyond six months post-vaccination, especially those aged 60 and above. These findings highlight the need for robust surveillance systems targeting new variants and administering booster doses, particularly for individuals aged 60 or older with underlying health conditions, to mitigate the global burden of COVID-19., Competing Interests: Declarations Ethics Approval The Clinical Research Ethics Committee of Andalusia (CCEIBA in Spanish) approved the research protocol for this study (010722 (Act 07/22), FPS-VAC-2022-01). This study was an epidemiological study including anonymized data, and the analysis was performed in Andalusian servers of the public healthcare system, and was not required to obtain informed consent from the patients. We conducted this study in accordance with the Declaration of Helsinki and the Spanish Law on the Protection of Personal Data and Guarantee of Digital Rights (3/2018 of December 5). Consent to Participate Not applicable. Competing Interests The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP . The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.

This study explores the production of bio-composites from barley, wheat, and cassava flours, reinforced with varying ratios of oil palm residues. The research emphasizes principles of circular economy and sustainability. Both flours and reinforcements underwent characterization to elucidate how their physicochemical properties affect the mechanical behavior of the bio-composites. Barley flour exhibited significantly higher levels of protein (11.11 %), crude fiber (5.64 %), and ash (2.80 %) compared to wheat and cassava flours. Conversely, cassava flour stood out for its high carbohydrate concentration (approximately 97.8 % on a dry weight basis). Characterization highlighted enhanced adhesion between reinforcements in bio-composites with cassava flour, alongside morphological distinctions on fractured surfaces. Fourier-transform infrared (FTIR) analysis unveiled several functional groups in the bio-composites, while thermogravimetric analysis delineated five stages of thermal degradation. In terms of mechanical properties, bio-composites with barley flour showed higher elastic modulus values (970.5 MPa), while those with 12 % OPKS exhibited tensile strengths of 1.7-2.1 MPa. The interaction among components emerged as a fundamental factor influencing the mechanical properties of bio-composites, underscoring the necessity of considering reinforcement composition and distribution during fabrication., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Prematurity is associated with an increased risk of persistent wheezing but the underlying mechanisms are not well defined. The aim of this study was to identify blood transcriptional profiles associated with the development of wheezing in a cohort of moderate to late preterm infants and to define immune gene expression changes associated with wheezing., Materials and Methods: A convenience sample of a multicenter birth cohort (SAREPREM) of moderate-late preterm children followed during the first 3 years of life was analyzed. Children were enrolled in the first 2 weeks of life (Y0) and longitudinally evaluated at 1 (Y1), 2 (Y2), and 3 years (Y3) of age, for the presence of wheezing and to obtain samples for transcriptional profile analysis. Samples were processed on Illumina HT12 chips and genomic expression analyses performed with R programming, modular analysis for biological function, and QuSAGE for quantitative gene expression., Results: Seventy-six children were included in the study; 33 were classified as non-wheezing and 43 (56.6%) in the wheezing group. At Y0, children who developed wheezing had decreased expression of interferon genes and increased expression of B cell genes compared with the non-wheezing group. These changes in IFN and B cell gene expression were especially significant in children with late/persistent wheezing compared with transient wheezers., Conclusions: Changes in IFN and B lymphocyte gene expression identified in early life suggest the existence of specific immunological mechanisms that play an important role in the development of wheezing in late-preterm infants., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Ensuring equitable access to adequate standard of care for patients with rare hematological disease is one of the aims of the European Reference Network (ERN) EuroBloodNet. Stroke is one of the most devastating complications for children with sickle cell disease (SCD). For effective prevention of stroke risk, annual transcranial Doppler (TCD) according to a defined protocol is recommended for patients aged 2-16 years, with red blood cell transfusion therapy for those at risk. There is no information regarding screening for stroke risk and stroke prevention programs in Europe., Methods: Seven SCD experts of five healthcare providers (HCPs) of ERN EuroBloodNet developed an online survey to assess the access to TCD screening and stroke prevention programs for children with SCD in Europe., Results: Eighty-one experts in 77 HCPs from 16 European countries responded to 16 online questions. Thirty-two of 77 (51%) HCPs were EuroBloodNet reference centers, and 36% physicians reported not having a dedicated TCD/TCD imaging service for children with SCD. Only 30% of physicians provided estimates that all their patients received annual TCD according to the standard protocol due to lack of trained staff (43%), lack of TCD instruments (11%), refusal of patients due to logistical difficulties (22%), and lack of funds for dedicated staff or equipment (11%)., Conclusions: This multinational European survey provides the first comprehensive picture of access to TCD screening and stroke prevention in European countries. Identifying the potential underlying causes of the lack of effective standardized screening, this survey also addresses possible dedicated actions to cover these needs., (© 2024 Wiley Periodicals LLC.)

Splenic infarction is a rare complication present in 7% of pancreatic inflammatory pathologies. This is justified by the close anatomical relationship between the pancreas and the splenic hilum. Although CT is considered the technique of choice for the diagnosis of this type of complications, the growing use of ultrasound in many digestive units, due to its accessibility and safety for patients, allows for early diagnosis and targeted treatment to prevent further complications. Splenectomy is reserved for cases where complications such as splenic abscess, spleen rupture, haemoperitoneum or persistent pain are present.

Background: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP., Methods: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed., Results: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion., Conclusion: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored., Methods: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume., Results: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes., Discussion: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks., Highlights: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Fibrosis is a chronic disease characterized by excessive extracellular matrix production, which leads to disruption of organ function. Fibroblasts are key effector cells of this process, responding chiefly to the pleiotropic cytokine transforming growth factor-β1 (TGF-β1), which promotes fibroblast to myofibroblast differentiation. We found that extracellular nutrient availability profoundly influenced the TGF-β1 transcriptome of primary human lung fibroblasts and that biosynthesis of amino acids emerged as a top enriched TGF-β1 transcriptional module. We subsequently uncovered a key role for pyruvate in influencing glutaminase (GLS1) inhibition during TGF-β1-induced fibrogenesis. In pyruvate-replete conditions, GLS1 inhibition was ineffective in blocking TGF-β1-induced fibrogenesis, as pyruvate can be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1 inhibition was required to fully block TGF-β1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

Introduction: Exposure to gases and particulate matter released during volcanic eruptions can prove harmful to population health. This paper reports the preliminary results of the ASHES study, aimed at ascertaining the respiratory health effects of the 2021 volcanic eruption in La Palma Island (Spain) on the adult population without previous respiratory disease., Methods: Ambispective cohort study on the healthy adult population. Three exposure groups were considered: Group 1, high exposure; Group 2, moderate exposure; and Group 3, minor or no exposure. We carried out a descriptive analysis of symptoms during and after the eruption, as well as measure lung function after the eruption (through forced spirometry and diffusing capacity of carbon monoxide)., Results: The analysis included 474 subjects: 54 in Group 1, 335 in Group 2, and 85 in Group 3. A significant increase in most symptoms was observed for subjects in the groups exposed during the eruption. After the eruption, this increase remained for some symptoms. There seems to be a dose-response relationship, such that the higher the exposure, the higher the odds ratio. A prebronchodilator FEV 1 /FVC ratio<70% was observed in 13.0% of subjects in Group 1, 8.6% of subjects in Group 2, and 7.1% of subjects in Group 3., Conclusions: This study is the first to report a dose-response relationship between exposure to volcanic eruptions and the presence of symptoms in adults. Furthermore, there is a tendency toward obstructive impairment in individuals with higher exposure., (Copyright © 2024 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments., (© 2024. The Author(s).)

Objective: Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiological biomarkers of HI and the association between the severity of such radiological alterations and post-BS weight loss (WL) trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEVs) enriched for microglial and astrocyte markers in studying HI was also explored., Research Design and Methods: We included 72 individuals with obesity (20 with and 52 without type 2 diabetes) and 24 control individuals. Participants underwent lumbar puncture and 3-T MRI at baseline and 1-year post-BS. We assessed hypothalamic mean diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEVs enriched for glial and astrocyte markers were determined by flow cytometry., Results: Compared with control group, the obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL 1 and 2 years after BS. CSF-lEVs did not differ among groups and were unrelated to WL trajectories., Conclusions: These findings suggest HI improvement after BS and may support a role for HI in modulating the WL response to these interventions., (© 2024 by the American Diabetes Association.)

Background: Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status and the presence of electrocardiographic and electrolytic disturbances., Objective: To identify factors associated with seven-day and thirty-day mortality in digoxin poisoning., Design, Settings and Participants: A retrospective, observational, multicenter study was conducted across 15 Hospital Emergency Departments (HED) in Spain. All patients over 18 years of age who presented to participating HEDs from 2015 to 2021 were included. The inclusion criteria encompassed individuals meeting the criteria for digoxin poisoning, whether acute or chronic., Outcomes Measure and Analysis: To identify independent factors associated with 7-day and 30-day mortality, a multivariate analysis was conducted. This analysis included variables of clinical significance, as well as those exhibiting a trend (p < 0.1) or significance in the bivariate analysis., Main Findings: A total of 658 cases of digoxin poisoning were identified. Mortality rates were 4.5% (30 patients) at seven days and 11.1% (73 patients) at thirty days. Regarding 7-day mortality, the mean age of deceased patients was comparable to survivors (84.7 (8.9) vs 83.9 (7.9) years; p = ns). The multivariate analysis revealed that factors independently associated with 7-day mortality encompassed the extent of dependence assessed by the Barthel Index (BI 60-89 OR 0.28; 95% CI 0.10-0.77; p = 0.014 and BI>90 OR 0.22; 95% CI 0.08-0.63; p = 0.005), the identification of ventricular arrhythmias (OR 1.34; 95% CI 1.34-25.21; p = 0.019), and the presence of circulatory (OR 2.84; 95% CI 1.19-6.27; p = 0.019) and neurological manifestations (OR 2.67; 95% CI 1.13-6.27; p = 0.025). Factors independently associated with 30-day mortality encompassed extent of dependence (BI 60-89 OR 0.37; 95% CI 0.20-0.71; p = 0.003 and BI>90 OR 0.18; 95% CI 0.09-0.39; p < 0.001) and the identification of circulatory (OR 2.13; 95% CI 1.10-4.15; p = 0.025) and neurological manifestations (OR 2.39; 95% CI 1.25-3.89; p = 0.006)., Conclusions: The study identifies the degree of dependency assessed by the Barthel Index and the presence of cardiovascular and neurological symptoms as independent predictors of both 7-day and 30-day mortality. Additionally, the detection of ventricular arrhythmia is also an independent factor for 7-day mortality., Competing Interests: Declaration of competing interest The authors report no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Agro-industrial residue valorization under the umbrella of the circular bioeconomy (CBE) has prompted the search for further forward-thinking alternatives that encourage the mitigation of the industry's environmental footprint. From this perspective, second-life valorization (viz., thermoplastic composites) has been explored for agro-industrial waste (viz., oil palm empty fruit bunch fibers, OPEFBFs) that has already been used previously in other circular applications (viz., the removal of domestic wastewater contaminants). Particularly, this ongoing study evaluated the performance of raw residues (R-OPEFBFs) within three different size ranges (250-425, 425-600, 600-800 µm) both before and after their utilization in biofiltration processes (as post-adsorbents, P-OPEFBFs) to reinforce a polymer matrix of acrylic resin. The research examined the changes in R-OPEFBF composition and morphology caused by microorganisms in the biofilters and their impact on the mechanical properties of the composites. Smaller R-OPEFBFs (250-425 µm) demonstrated superior mechanical performance. Additionally, the composites with P-OPEFBFs displayed significant enhancements in their mechanical properties (3.9-40.3%) compared to those with R-OPEFBFs. The combination of the three fiber sizes improved the mechanical behavior of the composites, indicating the potential for both R-OPEFBFs and P-OPEFBFs as reinforcement materials in composite applications.

Objectives: Precise HDV-RNA detection and quantification are pivotal for diagnosis and monitoring of response to newly approved treatment. We evaluate the performance of three HDV RNA detection and quantification assays., Methods: Hepatitis Delta RT-PCR system kit, EurobioPlex HDV assay, and RoboGene HDV RNA Quantification kit 2.0 were used for testing 151 HBsAg-positive samples, 90 HDV-RNA negative and 61 HDV-RNA positive. We also evaluated serial dilutions of the WHO international standard for HDV, PEI 7657/12. All HDV-RNA positive samples were genotyped using a next-generation sequencing strategy., Results: Qualitative results indicated a 100% concordance between tests. Quantitative results correlated well, r 2 = 0.703 (Vircell-vs-Eurobio), r 2 = 0.833 (Vircell-vs-RoboGene), r 2 = 0.835 (Robogene-vs-Eurobio). Bias index was 2.083 (Vircell-vs-Eurobio), -1.283 (Vircell-vs-RoboGene), and -3.36 (Robogene-vs-Eurobio). Using the WHO IS, Vircell overestimated the viral load by 0.98 log IU/mL, Eurobio by 1.46 log IU/mL, and RoboGene underestimated it by 0.98 log IU/mL. Fifty-nine samples were successfully genotyped (Genotype 1, n=52; Genotype 5, n=7; Genotype 6, n=1), with similar results for correlation and bias., Conclusion: This study underscores the necessity of using reliable HDV-RNA detection and quantification assays, as evidenced by the high concordance rates in qualitative detection and the observed variability in quantitative results. These findings highlight the importance of consistent assay use in clinical practice to ensure accurate diagnosis and effective treatment monitoring of HDV infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Illescas-López, Chaves-Blanco, de Salazar, Hernández-Febles, Carracedo, Lagarejos, Fuentes, Pereira, Cea, De La Iglesia, Freyre, Iborra, Odero, García-Barrionuevo, Aguilera, Pena and García.)

Malignant pleural effusion (MPE) has become an increasingly prevalent complication in oncological patients, negatively impacting their quality of life and casting a shadow over their prognosis. Owing to the pathophysiological mechanisms involved and the heterogeneous nature of the underlying disease, this entity is both a diagnostic and therapeutic challenge. Advances in the understanding of MPE have led to a shift in the treatment paradigm towards a more personalized approach. This article provides a comprehensive review and update on the pathophysiology of MPE and describes the diagnostic tools and the latest advances in the treatment of this complex clinical entity., (© 2024 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Background: The long-term survival of patients hospitalized with COVID-19 and the factors associated with poorer survival months after infection are not well understood. The aims of the present study were to analyze the overall mortality 10 months after admission., Methods: 762 patients with COVID-19 disease were included. Patients underwent a complete clinical evaluation, routine laboratory analysis and chest X-ray. Data collected included demographic and clinical data, such as vascular risk factors, tobacco or alcohol use, comorbidity, and institutionalization., Results: Ten-month mortality was 25.6%: 108 deaths occurred in-hospital, while 87 patients died after discharge. In-hospital mortality was independently related to NT-proBNP values > 503.5 pg/mL [OR = 4.67 (2.38-9.20)], urea > 37 mg/dL [3.21 (1.86-7.31)] and age older than 71 years [OR = 1.93 (1.05-3.54)]. NT-proBNP values > 503.5 pg/mL [OR = 5.00 (3.06-8.19)], urea > 37 mg/dL [3.51 (1.97-6.27)], cognitive impairment [OR = 1.96 (1.30-2.95), cancer [OR = 2.23 (1.36-3.68), and leukocytes > 6330/mm 3 [OR = 1.64 (1.08-2.50)], were independently associated with long-term mortality., Conclusions: the risk of death remains high even months after COVID-19 infection. Overall mortality of COVID-19 patients during 10 months after hospital discharge is nearly as high as that observed during hospital admission. Comorbidities such as cancer or cognitive impairment, organ dysfunction and inflammatory reaction are independent prognostic markers of long-term mortality.

Background & Aims: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT)., Methods: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT., Results: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates., Conclusion: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors., Impact and Implications: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer's disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ana Martinez, Valle Palomo reports financial support was provided by AEI. Ana Martinez, Valle Palomo reports financial support was provided by La Caixa and Luzón Foundation. If there are other authors, they 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that 2 distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a potentially novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice livers, dual AAV gene therapy combined with rapamycin reduced the effect of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and to support clinical translation.

Poor sleep quality, a global public health concern, poses a significant burden on individuals, particularly health care university students facing intense academic stress. A three-center cross-sectional study was conducted at the Higher Institute of Nursing and Health Sciences in Tetouan (Morocco), Faculty of Medicine in Tangier (Morocco) and Faculty of Nursing in Valencia (Spain). We collected various data using a sociodemographic questionnaire, the Pittsburgh sleep quality questionnaire, the international physical activity questionnaire (IPAQ) and the smartphone addiction questionnaire short-version (SAS-SV). A total of 1210 students were included in our study (mean age 20.4 years, 67.2% female, nursing students (66.2%) and medical students (33.8%), 76.1% students from Morocco and 33.9% from Spain). Analysis revealed a higher prevalence of poor sleep quality among Moroccans students compared to Spanish ones ( p < 0.001), that nursing students showed less favorable sleep quality than medical students ( p < 0.011) and that living with a chronic disease was linked to less favorable sleep quality ( p < 0.001). Lastly, intense or weak physical activity and smartphone addiction were correlated with poor sleep quality ( p < 0.001). In the multivariate analysis, an association persisted between poor sleep quality and factors such as the country of study (Odds ratio (OR): 6.25 [95% Confidence Interval (CI): 4.34-9.09]), involvement in nursing studies (OR: 3.50 [95% CI: 2.36-5.27]), and the presence of chronic diseases (OR: 2.70 [95% CI: 1.72-4.16]), ( p < 0.01 each). Our findings highlight the multifaceted factors affecting sleep quality in young university students. The implications underscore the imperative of interventions tailored to this demographic group.

Anxiety is an important and recurrent problem in people with severe mental illness (SMI). The aim of this work is to measure the effectiveness of the Music Therapy nursing intervention in reducing anxiety in outpatients diagnosed with SMI (bipolar disorder and schizophrenia). The intervention was structured over five weeks (ten 1-h sessions, twice weekly). Objective measures (blood pressure, heart rate, and respiratory rate) and subjective measures (anxiety response and the subjective perception of relaxation) were taken before and after every session. Our results show that this nursing intervention entails an objective reduction of the respiratory rate ((-4.5, -0.5) breaths per minute), the heart rate ((-5.80, -2.13) bpm), and it evidences a reduction in the subjective perception of anxiety (16.08% mean reduction in state anxiety). Considering all the sessions, the subjective perception of relaxation increased 97.33% of the time. This study provides evidence that the Music Therapy intervention can effectively promote relaxation and reduce anxiety symptoms in people with SMI. This study was retrospectively registered at Clinical Trials with Protocol Identifier NCT06315049.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without a cure to reverse its progression. Its main hallmark is the nuclear protein TDP-43, which undergoes different post-translational modifications leading to a loss of function in the nucleus and an increase in toxicity in the cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation in various contexts. With the aim of advancing therapeutics focused on preventing the propagation of TDP-43 pathology, we studied the potential role of pathogenic TDP-43 in lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines from sporadic ALS patients as a source of pathogenic forms of TDP-43, and healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) as recipient cells to investigate the seeding and spread of TDP-43 proteinopathy. Furthermore, we evaluated the potential of targeting TDP-43 phosphorylation with a CK-1 inhibitor to prevent the propagation of the pathology. The results presented herein indicate that pathogenic forms of TDP-43 are secreted into the extracellular medium of sporadic ALS lymphoblasts and could be transported by extracellular vesicles, spreading TDP-43 pathology to healthy cells. Moreover, tunneling nanotubes have also been discovered in pathological cells and may be involved in the transport of TDP-43. Interestingly, targeting TDP-43 phosphorylation with an in-house designed CK-1 inhibitor (IGS2.7) was sufficient to halt TDP-43 pathology transmission, in addition to its known effects on restoring the homeostasis of TDP-43 protein in patients-derived cells., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA)., Methods: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level., Results: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R 2  = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912)., Conclusion: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset., (© 2023. The Author(s).)

Introduction: Recent evidence reported mental health issues in university students such as anxiety and depressive symptoms and poor sleep quality. Decreased plasma brain-derived neurotrophic factor (BDNF) levels have been proposed as a biomarker of depressive symptoms, whereas cortisol levels are an index of energy mobilization and stress and have been linked to sleep quality. Given that salivary biomarkers represent an interesting new field of research, the aim of this cross-sectional study was to evaluate salivary BDNF and cortisol levels in university students to assess whether they have associations with psychological disturbances such as anxiety and depressive symptoms, sleep quality, and stress level., Methods: Salivary BDNF and cortisol levels were measured by specific immunoassays in 70 students whose mental health was also evaluated on the same day through the evaluation of anxiety and depression symptoms (Goldberg scale), sleep quality (Pittsburg Sleep Quality Index and Athens Insomnia Scale), and stress (self-perceived stress scale) and healthy lifestyle habits (alcohol consumption, smoking, regular exercise, and body mass index) were also measured. Multivariate regression analyses were performed in order to identify the strengths of associations between psychological alterations and the concentrations of BDNF, cortisol, and other variables., Results: Salivary BDNF levels were significantly higher in students with more depressive symptoms, whereas no significant differences were found for cortisol levels. When performing the binary logistic regression model, BDNF levels are included as a predictor variable for a high-depressive-symptoms burden ( p < 0.05). Students with worse sleep quality on the Pittsburg Scale had higher cortisol levels ( p < 0.05). The subdomains of sleep latency and sleep medication were those significantly associated with salivary cortisol levels in logistic regression analyses (OR = 15.150, p = 0.028). Sleep medication only appeared to be related to cortisol levels (OR = 185.142, p = 0.019). Perceived stress levels and anxiety symptoms were not associated with BDNF or cortisol levels., Conclusions: BDNF could play a key role in the pathophysiology of mood-related disorders, and elevation of its peripheral levels could contribute to protecting neurons from the development of mental illness. Higher salivary cortisol levels measured in the morning are accompanied by poorer sleep quality. More research is needed, focusing on salivary biomarkers of disorders related to depressive symptoms and poor sleep quality as a potential tool for the diagnosis and prevention of mental illness.

Microplastic (MP) accumulation in the environment is accelerating rapidly, which has led to their effects on both the ecosystem and human life garnering much attention. This study is the first to examine the degradation of high-density polyethylene (HDPE) MPs via photoelectrocatalysis (PEC) using a TiO 2 -modified boron-doped diamond (BDD/TiO 2 ) photoanode. This study was divided into three stages: (i) preparation of the photoanode through electrophoretic deposition of synthetic TiO 2 nanoparticles on a BDD electrode; (ii) characterization of the modified photoanode using electrochemical, structural, and optical techniques; and (iii) degradation of HDPE MPs by electrochemical oxidation and photoelectrocatalysis on bare and modified BDD electrodes under dark and UV light conditions. The results indicate that the PEC technique degraded 89.91 ± 0.08% of HDPE MPs in a 10-h reaction and was more efficient at a lower current density (6.89 mA cm -1 ) with the BDD/TiO 2 photoanode compared to electrochemical oxidation on bare BDD., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus-derived (rAAV-derived) vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs. Among them, an N-terminal-truncated mutant, ΔNter2-GDE, had a similar efficacy in vivo compared with the full-size enzyme. A rAAV vector expressing ΔNter2-GDE allowed significant glycogen reduction in heart and muscle of Agl-/- mice 3 months after i.v. injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agl-/- rat model. Finally, transduction with rAAV vectors encoding ΔNter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to patients with GSDIII.

Introduction: The existing body of literature on the biomechanical implications of ramp lesions is limited, leaving a significant gap in our understanding of how these lesions impact joint kinematics and loading in the medial compartment. This cadaveric biomechanical study aims to address this gap by employing an innovative Digital Volume Correlation (DVC) method, utilizing 7 Tesla Magnetic Resonance Imaging (MRI) images under various loading conditions. The primary objective is to conduct a comprehensive comparison of medial meniscal mobility between native knees and knees affected by grade 4 ramp lesions. By focusing on the intricate dynamics of meniscal mobility and extrusion, this work seeks to contribute valuable insights into the biomechanical consequences of medial meniscus ramp lesions. Materials and methods: An initial set of 7T MRI imaging sessions was conducted on two intact native knees, applying load values up to 1500N. Subsequently, a second series of images was captured on these identical knees, with the same loads applied, following the creation through arthroscopy of medial meniscus ramp lesions. The application of DVC enabled the precise determination of the three components of displacement and spatial variations in the medial menisci, both with and without ramp lesions. Results: The measured directional displacements between native knees and injured knees indicate that, following the application of axial compression load, menisci exhibit increased extrusion and posterior mobility as observed through DVC. Discussion: Injuries associated with Subtype 4 medial meniscus ramp lesions appear to elevate meniscal extrusion and posterior mobility during axial compression in the anterior cruciate ligament of intact knees. Following these preliminary results, we plan to expand our experimental approach to encompass individuals undergoing weight-bearing MRI. This expansion aims to identify meniscocapsular and/or meniscotibial insufficiency or rupture in patients, enabling us to proactively reduce the risk of osteoarthritic progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Severyns, Zot, Harika-Germaneau, Germaneau, Herpe, Naudin, Valle, Danion and Vendeuvre.)

Background: Poor sleep quality is prevalent in older people and impairs their quality of life. Various studies show an association between sleep disorders and altered levels of inflammatory cytokines. The cytokine IL-1β has been shown to display both somnogenic and insomnia-promoting effects in experimental animals. Objectives: to evaluate the relationship between insomnia and salivary IL-1β concentration and the role of associated factors such as the symptoms of depression, use of hypnotics, intake of caffeinated beverages, smoking, and alcohol use in older individuals. An analytical, cross-sectional, observational research was carried out with a population of community-dwelling individuals over 60 years of age in Valencia (Spain). Sleep quality was measured with the Athens insomnia scale (AIS) and depressive symptoms with Geriatric Depression Scale (GDS). Results: 287 individuals participated in the study (mean age 74.08 years (76.7% women). 41.5% of the participants had insomnia, 36.9% took drugs for sleep problems, and 32.4% had relevant depressive symptoms. There was a significant inverse correlation between the IL-1β and total AIS score (rho = -0.302, p < 0.001), the sleep difficulty subdomain (rho = -0.259, p < 0.001), and the daytime sleepiness subdomain (rho = -0.322, p < 0.001). No significant correlation was observed between GDS and salivary IL-1β concentration. The IL-1β concentration was significantly lower in individuals taking drugs for sleeping compared with those not taking those drugs (1.11 ± 0.09 and 1.48 ± 0.08, respectively; p = 0.001). Regarding the AIS score, there was no significant difference in marital status, smoking, or the number of cups of tea or cola drinks, but there was a significant association with alcohol intake ( p = 0.019) and in the number of daily intakes of coffee ( p = 0.030). The receiver operating characteristic (ROC) curve analysis of IL-1β for diagnosis of moderate-severe insomnia showed an area under the curve (AUC) value of 0.78 (95% confidence interval 0.71-0.85). At the cut-off of 0.83 pg/µL of Il-1β, it had a sensitivity of 70.3% and a specificity of 69.8%., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties., Methods: Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS., Results: One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord., Conclusions: For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

During the COVID-19 pandemic, there were reports of heightened levels of anxiety and fear of contagion in the general population. Such psychological responses may be influenced by the socio-environmental context in which individuals reside. This study aimed to examine the relationship between socioeconomic and educational factors and the level of anxiety and fear related to COVID-19. A multicenter, cross-sectional design was used, including patients aged 18 years or older who attended primary care physician consultations at various primary health centers in Toledo, Spain, between October 2020 and January 2021. By means of a non-probabilistic sampling, a total of 150 participants were selected for the study, with 146 of them providing responses to the AMICO questionnaire The level of fear and anxiety associated with COVID-19 was assessed using the validated Anxiety and Fear of COVID-19 Assessment Scale (AMICO). A significant linear relationship was revealed between social class, employment status, and anxiety levels. Specifically, as social class decreased ( p = 0.001) and employment situation worsened (unemployment) ( p = 0.037), the proportion of participants reporting a high level of anxiety increased. During the second phase of the pandemic, more than half of the patients attending family medicine consultations exhibited a high level of fear and anxiety towards COVID-19, which was significantly associated with lower social class and unemployment.

Background: Nursing and midwifery students do not feel adequately prepared during their clinical training to support women who breastfeed, demanding more effective communication skills and knowledge., Aim: The aim was to evaluate changes in students' breastfeeding knowledge., Methods: This was a mixed-methods quasi-experimental design. Forty students voluntarily participated. Using a 1:1 ratio, 2 groups were randomly created and completed the validated questionnaire ECoLaE (pre-post). The educational program consisted of focus groups, a clinical simulation, and a visit to the local breastfeeding association., Findings: The control group's posttest scores ranged from 6 to 20 (mean = 13.1, standard deviation [SD] = 3.0). The intervention group ranged from 12 to 20 (mean = 17.3, SD = 2.3). A Student's t test for independence samples was calculated ( P < .005, t = 4.5, median = 4.2). The intervention group had a mean difference of 10 points in improvement (mean =10.53, SD = 2.20, min = 7, max = 14), whereas the control group had a mean of 6 points (mean = 6.80, SD = 3.03, min = 3, max = 13). The multiple linear regression explained the intervention's effect. The regression model had statistical significance ( F = 4.87, P = 0.004), with an adjusted R2 = 0.31. The linear regression between the posttest scores and group variables after adjusting by age showed an increment of 4.1 points in the intervention posttest scores ( P < .005, 95% confidence interval [CI] = 2.1-6.1)., Conclusions: The educational program "Engage in breaking the barriers to breastfeeding" improved nursing students' knowledge., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

Objectives: The aims of this study in the Emergency Department and Elder Needs (EDEN) series were to explore associations between clinical variables on arrival at the ED (baseline) and the insertion of a bladder catheter, and the relation between catheterization and deterioration to a more complex or serious clinical state., Material and Methods: Included were all patients aged 65 years or older attended during 1 week in 52 Spanish EDs. Patients were grouped according to whether a bladder catheter was or was not inserted in the ED. We used multivariable logistical regression to explore associations between catheterization and patient age, sex, 10 comorbidities, 7 baseline status variables, and 6 clinical variables. Progression was considered serious or complex if the patient died or required hospitalization, a prolonged hospital stay, or discharge to a care facility. We also explored the association between age and catheterization using adjusted restricted cubic spline (RCS) curves with a cutoff value of 65 years., Results: Participating hospitals enrolled 24 573 patients; bladder catheters were inserted in 976 (4%). Of these, 44.3% were discharged from the ED. Fifteen of the 24 variables were independently associated with bladder catheterization. Factors with the strongest associations according to odds ratios (ORs) were impaired consciousness (OR, 2.50; 95% CI, 1.90-3.30), dehydration (OR, 2.24; 95% CI, 1.85-2.72), and male sex (OR, 2.12; 95% CI, 1.84- 2.44). Age 80 years or older was also associated with bladder catheterization (OR, 1.17; 95% CI, 1.01-1.358). The adjusted RCS curves showed a progressive linear increase in the probability of catheterization with age. The increase was constant in men and stabilized after the age of 85 years in women (P-interaction .001). Bladder catheterization was associated with hospitalization (OR, 2.31; 95% CI, 1.99-2.68), intensive care unit admission (OR, 4.64; 95% CI, 3.04-7.09), prolonged stay in the ED for discharged patients (OR, 2.28; 95% CI, 1.75-2.96), in-hospital death (OR, 1.99; 95% CI, 1.54-2.57), and 30-day death (OR, 1.66; 95% CI, 1.33-2.08). No associations were found between catheterization and prolonged hospital stay (OR, 1.11; 95% CI, 0.92-1.34) or need for a care facility on discharge (OR, 1.50; 95% CI, 0.98-2.29)., Conclusion: Certain patient characteristics and baseline clinical conditions are associated with bladder catheterization in patients of advanced age. The main factors were decreased consciousness, dehydration, and male sex. Even after adjustment for related factors, catheterization is independently associated with progression to more complex or serious clinical states.

Background & Aims: Life-long hepatocellular carcinoma (HCC) surveillance is recommended after sustained virological response (SVR) in patients with advanced hepatitis C. Since the identification of patients who could be safely discontinued for surveillance is essential, we aimed to identify subsets of patients with low-risk HCC., Methods: 491 patients with advanced and compensated fibrosis (≥F3) were prospectively followed after achieving SVR with interferon-free therapies. Clinical-biological parameters and liver stiffness measurement (LSM) were performed before starting treatment (ST) and at SVR, and HCC surveillance was carried out., Results: During a median follow-up of 49.8 months, 29 (5.9%) patients developed HCC [incidence rate: 1.6/100 patient-years (PYs)]. Two predictive models based on LSM (Model-A) or FIB-4 score (Model-B) were proposed. Only SVR parameters were included in the models, because they showed a higher accuracy for predicting HCC than ST measurements. Variables independently associated with HCC were LSM (HR, 1.03; 95% CI, 1.01-1.05), age (HR, 1.04; 95% CI, 1.01-1.08) and albumin levels (HR, 0.90; 95% CI, 0.84-0.97) in Model-A, and FIB-4 (HR, 1.22; 95% CI, 1.08-1.37) and albumin (HR, 0.90; 95% CI, 0.84-0.97) in model-B. Both models allow HCC risk stratification, identifying low-risk groups with an HCC incidence rate of 0.16/100 and 0.25/100 PYs, respectively. An overall increased hazard of HCC was observed over time., Conclusion: Simple models based on non-invasive markers of liver fibrosis, LSM or FIB-4, together with age and albumin levels at SVR permit to identify subsets of patients with HCC risk clearly <1%/year, for whom HCC surveillance might not be cost-effective., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Introduction: This study evaluated the effect of a surgical opioid-avoidance protocol (SOAP) on postoperative pain scores. The primary goal was to demonstrate that the SOAP was as effective as the pre-existing non-SOAP (without opioid restriction) protocol by measuring postoperative pain in a diverse, opioid-naive patient population undergoing inpatient surgery across multiple surgical services., Methods: This prospective cohort study was divided into SOAP and non-SOAP groups based on surgery date. The non-SOAP group had no opioid restrictions (n=382), while the SOAP group (n=449) used a rigorous, opioid-avoidance order set with patient and staff education regarding multimodal analgesia. A non-inferiority analysis assessed the SOAP impact on postoperative pain scores., Results: Postoperative pain scores in the SOAP group compared with the non-SOAP group were non-inferior (95% CI: -0.58, 0.10; non-inferiority margin=-1). The SOAP group consumed fewer postoperative opioids (median=0.67 (IQR=15) vs 8.17 morphine milliequivalents (MMEs) (IQR=40.33); p<0.01) and had fewer discharge prescription opioids (median=0 (IQR=60) vs 86.4 MMEs (IQR=140.4); p<0.01)., Discussion: The SOAP was as effective as the non-SOAP group in postoperative pain scores across a diverse patient population and associated with lower postoperative opioid consumption and discharge prescription opioids., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Robotic distal pancreatectomy (RDP) is associated with a lower conversion rate and less blood loss than laparoscopic distal pancreatectomy (LDP). LDP has similar oncological outcomes as open surgery in PDAC. The aim of this study was to compare perioperative and oncological outcomes in obese patients with RDP versus LDP for PDAC., Materials and Methods: Retrospectively, all obese patients who underwent RDP or LDP for PDAC between 2012 and 2022 at 12 international expert centres were included., Results: out of 372, 81 patients were included. All baseline features were comparable between the two groups. RDP was associated with decreased blood loss (495mlLDP vs. 188mlRDP; p = 0.003), lower conversion rate (13.5%RDP vs. 36.4%LDP; p = 0.019) and lower rate of Clavien-Dindo ≥3 complications (13.5%RDP vs. 36.4%LDP; p = 0.019). Overall and disease-free survival were comparable., Conclusions: In obese patients with left-sided PDAC, the robotic approach was associated with improved intraoperative outcomes and fewer severe complications., (© 2023 John Wiley & Sons Ltd.)

Background: Although robotic distal pancreatectomy (RDP) has a lower conversion rate to open surgery and causes less blood loss than laparoscopic distal pancreatectomy (LDP), clear evidence on the impact of the surgical approach on morbidity is lacking. Prior studies have shown a higher rate of complications among obese patients undergoing pancreatectomy. The primary aim of this study is to compare short-term outcomes of RDP vs. LDP in patients with a BMI ≥ 30., Methods: In this multicenter study, all obese patients who underwent RDP or LDP for any indication between 2012 and 2022 at 18 international expert centers were included. The baseline characteristics underwent inverse probability treatment weighting to minimize allocation bias., Results: Of 446 patients, 219 (50.2%) patients underwent RDP. The median age was 60 years, the median BMI was 33 (31-36), and the preoperative diagnosis was ductal adenocarcinoma in 21% of cases. The conversion rate was 19.9%, the overall complication rate was 57.8%, and the 90-day mortality rate was 0.7% (3 patients). RDP was associated with a lower complication rate (OR 0.68, 95% CI 0.52-0.89; p = 0.005), less blood loss (150 vs. 200 ml; p < 0.001), fewer blood transfusion requirements (OR 0.28, 95% CI 0.15-0.50; p < 0.001) and a lower Comprehensive Complications Index (8.7 vs. 8.9, p < 0.001) than LPD. RPD had a lower conversion rate (OR 0.27, 95% CI 0.19-0.39; p < 0.001) and achieved better spleen preservation rate (OR 1.96, 95% CI 1.13-3.39; p = 0.016) than LPD., Conclusions: In obese patients, RDP is associated with a lower conversion rate, fewer complications and better short-term outcomes than LPD., (© 2023. The Author(s).)

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8 + T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation., (© 2023. The Author(s).)

Objectives: To evaluate the impact of a mentoring programme for medical students doing a palliative care rotation, aimed at improving coping with death and attitudes towards the suffering produced by illness., Methods: A quasi-experimental study without a control group was carried out on second-year medical students. Five 1-h group sessions were conducted. Attitudes towards grief and coping with death were assessed before the mentoring programme began and afterwards, using the Brief Humanizar Scale and the Bugen's Coping with Death Scale, respectively., Results: In terms of the sense of grieving as measured by the Brief Humanizar Scale, the mean score for the 'Burden' factor was 7 points and for the 'Change' factor it was 28.6, indicating that suffering makes more sense as a lever for positive change than as a burden. Regarding Bugen's Coping with Death Scale, the mean score was 127.8 points before the mentoring programme and 139.2 afterwards. Hence, the score after the mentoring programme increased by 11.4 points, improving strategies to cope with death., Conclusion: Medical professionals must cope with death and end-of-life patients. In addition to scientific knowledge, students need to acquire competencies for better coping with the death of patients, with mentoring programmes helping to enhance this process of learning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Poor sleep quality is a major public health concern for all ages. In particular, university students often face stress levels and changes in social life habits that negatively influence their quality of sleep. This could be associated with psychological well-being in terms of anxiety and depressive symptoms, stress levels, and a poor self-perceived health status. The increases in the pro-inflammatory cytokine interleukin 6 (IL-6), IL-1 beta (IL-1β), and tumor necrosis factor alpha (TNFα), in blood have been linked to poor sleep quality in many diseases, but data on salivary cytokine levels in students are missing or are seldom analyzed. In this study we determined the quality of sleep in a sample of university students and the role of psychological assessment and factors affecting sleep (alcohol intake, tobacco, consumption of stimulant drinks, exercise, and body mass index). We also aimed to shed new light on the associations between sleep quality and salivary inflammatory cytokines (IL-1β, IL-6, and TNFα). Sleep quality was measured with the Athens Insomnia Scale (AIS) and Pittsburgh Sleep Quality Index (PSQI). Perceived stress was assessed using Cohen's Perceived Stress Scale (PSS), and the Goldberg Anxiety and Depression Scale (GADS) was used to assess the level of anxiety or depression. Perceived health status was measured with a visual analogue. Saliva samples was taken in the morning and the inflammatory cytokines was measured via enzyme-linked immunoassay. There was a direct and significant association between the salivary IL-1β concentration and AIS score (r = 0.248; p = 0.038, Pearson correlation) and Pittsburgh scale score (r = 0.274; p = 0.022, Pearson correlation). The relationship between IL-1β and AIS controlling for sex, age, and chronic disease, is still significant (r = 0.260; p = 0.033). The relationship between IL-1β and PSQI controlling for the influence of these variables is also significant (r = 0.279; p = 0.022). Salivary IL-1β concentrations were not significantly associated with any of the scores of the other psychological assessments (PSS, anxiety, depression symptoms, or self-perceived health). Salivary TNFα was significantly and inversely associated with self-perceived health (r = -0.259; p = 0.033, Pearson correlation), but the salivary IL-6 concentration was not associated with any of the sleep quality scale or psychological assessment scores. Our results provide a novel relationship between pro-inflammatory cytokine IL-1β in saliva and poor sleep quality. However, the role of inflammation in poor sleep quality requires further study to identify strategies that could lower inflammation and thus, likely improve sleep quality.

Background: Cardiac dysfunction (CD) has emerged as a key contributor to delayed organ failure and late mortality in patients surviving the initial traumatic hemorrhagic response. Inflammatory processes are implicated in the initial stages of this CD; however, downstream pathways leading to a characteristic rapid fall in stroke volume and cardiac output are not yet fully defined. Currently, no cardioprotective treatments are available. We investigated the role of myocardial oxidative stress in the pathogenesis of CD associated to traumatic hemorrhagic injury, and its related metabolomic profile., Methods: Ex vivo tissue from a 3-hour murine model of pressure-controlled trauma hemorrhagic shock (THS) was analyzed. Animals were randomized to echocardiography-guided crystalloid fluid resuscitation or a control group (sham: cannulation and anesthesia only, or naïve: no intervention). Trauma hemorrhagic shock and naïve samples were assessed by immunohistochemistry for nuclear 8-hydroxy-2'-deoxyguanosine expression as a marker of oxidative stress. Metabolomic analysis of THS and sham group tissue was performed by LC-MS., Results: 8-Hydroxy-2'-deoxyguanosine expression across the myocardium was significantly higher following THS injury compared to naïve group (33.01 ± 14.40% vs. 15.08 ± 3.96%, p < 0.05). Trauma hemorrhagic shock injury significantly increased lysine ( p = 0.022), and decreased aconitate ( p = 0.016) and glutamate ( p = 0.047) in the myocardium, indicating activation of a catabolic metabolism and oxidative stress response., Conclusion: We confirm the acute development of oxidative stress lesions and altered cardiac energy metabolism following traumatic hemorrhage injury, providing insight into the relationship between inflammatory damage and impaired cardiac contractility. These findings may provide targets for development of novel cardioprotective therapeutics aiming to decrease late mortality from trauma., (Copyright © 2023 American Association for the Surgery of Trauma.)

Objectives: Digoxin toxicity accounts for a small percentage of poisonings attended by emergency departments. This study aimed to describe differences between acute and chronic digoxin toxicity and assess the use of digoxin-specific antibody fragments (digoxin-Fab) as an antidote., Material and Methods: Retrospective, observational, multicenter study in 15 hospital emergency departments in 8 Spanish autonomous communities in 7 years. We collected patient, clinical and treatment variables, and discharge destination. Patients were classified according to whether toxicity was acute or chronic and whether digoxin-Fab was administered or not., Results: Twenty-seven acute and 631 chronic digoxin poisonings were attended. The mean (SD) patient age was 83.9 (7.9) years, and 76.9% were women. Patients with acute toxicity were younger (80.0 [12] years) than those with chronic toxicity (84.1 [7.7] years) (P .038), and accidental poisoning was less common (in 85.2% vs 100% in chronic toxicity; P .001). Cases of acute toxicity were also more serious (Poison Severity Score (29.6% vs 12.5% in chronic toxicity; P .001). Thirty-four patients were treated with digoxin-Fab (5.4%). These patients were younger (78.7 [11.5] years vs 84.2 (7.6) years), their toxicity was more often acute (in 20.6% vs 3.2% in chronic toxicity), more had attempted suicide (8.8% vs 0.2% with chronic toxicity), and more had severe symptoms (50% vs 11.2%) (P .001, all comparisons). Hospital admission was required for 76.1%. Overall, mortality was 11.4%., Conclusion: Chronic toxicity accounts for most digoxin poisoning cases, and most patients are women. Acute toxicity is more serious. Patients who required digoxin-Fab have more severe poisoning. Such patients usually have acute toxicity, and attempted suicide is more often the reason for the emergency.

Introduction: TDP-43 proteinopathy in Alzheimer's disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism., Methodology: We have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments., Results: TDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs., Conclusion: TTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martinez-Gonzalez, Cuevas, Tosat-Bitrián, Nozal, Gil, Palomo, Martín-Requero and Martinez.)

Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted., Competing Interests: Declaration of interests MdMMP declares grant funding or contracts from EuroBloodNet Association (RADeep) and Agios Pharmaceuticals (PKDeep) and participation in an advisory board for Agios Pharmaceuticals. RC declares grant funding or contracts from Global Blood Therapeutics, EU grants in the framework of Horizon 2020 and Horizon Europe, and EuroBloodNet Association (RADeep); consulting fees from Global Blood Therapeutics and Novartis; honoraria from Physician's Education Resources and Global Blood Therapeutics; participation on a data safety monitoring board or advisory board for Vertex, Addmedica, and Novonordisk; being a member of the steering committee of the Italian Association of Pediatric Hematology Oncology and coordinator of the Red Cell Disorder Working Group. PB declares grant funding or contracts from EuroBloodNet Association (RADeep). EC declares support for the Spanish Registry of Rare Anemias, partly supported by Novartis; grant funding or contracts from Vall d'Hebrin Research Institute (Integra) and EuroBloodNet Association (RADeep); honoraria from Terumo BCT, Chiesi, and Bionest; support for attending meetings or travel to the European Hematology Association Hemoglobinopathy Working Party 2023 by the European Hematology Association and to the Sociedad Española de Hematología y Oncología Pediátricas 2022 by Novartis; and participation on a data safety monitoring board or advisory board of Novartis (Adakveo) and Vertex. AC declares grant funding or contracts from EuroBloodNet Association (RADeep) and consulting fees from Novartis. LD declares grant funding or contracts from EuroBloodNet Association (RADeep). AG declares grant funding or contracts from Bristol Myers Squibb, Novo Nordisk, and EuroBloodNet Association (RADeep) and participation on a data safety monitoring board or advisory board of Novo Nordisk and Agios Pharmaceuticals. VGV declares grant funding or contracts from EuroBloodNet Association (RADeep). AK declares grant funding or contracts from Novartis and BMS; consulting fees from Agios Pharmaceuticals, Amgen, Bristol Myers Squib/Celgene, Crispr/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor; honoraria from Novartis, Bristol Myers Squib/Celgene, Chiesi, and Crisp/Vertex; and support for attending meetings or travel from Bristol Myers Squib/Celgene. JK declares grant funding or contracts from the Deutsche Kinderkrebsstiftung (German Childhood Cancer Foundation), Pfizer, and Novartis; support for attending meetings or travel for American Society of Hematology Annual Meeting 2020 with support from Art Tempi Communications; participation on a data safety monitoring board or advisory board of Novartis, Global Blood Therapeutics, and Bluebird Bio; and leadership or fiduciary role of the Konsortium Sichelzellkrankheit. SL declares consulting fees for advisory board of Novartis, BlueBird Bio, AddMedica, Global Blood Therapeutics, and Agios; honoraria from Novartis and BlueBird Bio; participation on a data safety monitoring board or advisory board of Novartis, BlueBird Bio, AddMedica, Global Blood Therapeutics, and Agios; leadership or fiduciary role at Vertex CTX001 study program steering committee, in the German National Disease Management Program, and in the German National Treatment Guideline. SR declares grant funding or contracts from EuroBloodNet Association (RADeep). GR declares participation on a data safety monitoring board or advisory board of Biovalley. MS declares payment for expert testimony from Novartis; support for attending meetings or travel to ASCAT 2022 from ERN-EuroBloodNet; leadership or fiduciary role as patient representative for the UK in the Red Cell Network, Patient and Public Voice Group. EvB declares grant funding or contracts from Agios Pharmaceuticals, Horizon Europe, Sikkelcelfonds, and EuroBloodNet Association (RADeep); honoraria from Agios and GSK; support for attending meetings or travel from European Rare Disease Research Coordination and Support Action consortium and EuroBloodNet Association (RADeep); participation on a data safety monitoring board or advisory board at Imara, BMS, Agios, and Forma therapeutics; leading the ERN-EuroBloodNet Transversal Field of Action on Clinical Trials and Research for non-oncological rare haematological diseases; and being a board member of the Benign Hematology Section of the Dutch Society for Hematology (NVVH) and chair of the Dutch Patient Registry for Sickle Cell Disease (SCORE). PK declares grant funding or contracts from EuroBloodNet Association (RADeep). BG declares grant funding or contracts from EuroBloodNet Association (RADeep). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objective: Robotic distal pancreatectomy (DP) is an emerging attractive approach, but its role compared with laparoscopic or open surgery remains unclear. Benchmark values are novel and objective tools for such comparisons. The aim of this study was to identify benchmark cutoffs for many outcome parameters for DP with or without splenectomy beyond the learning curve., Methods: This study analyzed outcomes from international expert centers from patients undergoing robotic DP for malignant or benign lesions. After excluding the first 10 cases in each center to reduce the effect of the learning curve, consecutive patients were included from the start of robotic DP up to June 2020. Benchmark patients had no significant comorbidities. Benchmark cutoff values were derived from the 75th or the 25th percentile of the median values of all benchmark centers. Benchmark values were compared with a laparoscopic control group from 4 high-volume centers and published open DP landmark series., Results: Sixteen centers contributed 755 cases, whereof 345 benchmark patients (46%) were included the analysis. Benchmark cutoffs included: operation time ≤300 minutes, conversion rate ≤3%, clinically relevant postoperative pancreatic fistula ≤32%, 3 months major complication rate ≤26.7%, and lymph node retrieval ≥9. The comprehensive complication index at 3 months was ≤8.7 without deterioration thereafter. Compared with robotic DP, laparoscopy had significantly higher conversion rates (5×) and overall complications, while open DP was associated with more blood loss and longer hospital stay., Conclusion: This first benchmark study demonstrates that robotic DP provides superior postoperative outcomes compared with laparoscopic and open DP. Robotic DP may be expected to become the approach of choice in minimally invasive DP., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)