GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.

Disruptions in circadian rhythms are associated with increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole-body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24 h feeding fasting cycle. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a Control or leucine-devoid diet (LeuD) for 8-days in total darkness. On the last day, blood and livers were collected at circadian time (CT) 3 and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched chain amino acid concentrations (r2=0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillation in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Further, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole-body metabolism.

[Use of physical restraints in the elderly in an emergency department. Analysis of clinical, environmental and health care team organization factors associated with decision making]. / Uso de sujeciones físicas en ancianos atendidos en un servicio de urgencias. Análisis de los factores clínicos, del entorno y de la organización del equipo sanitario asociados en la toma de decisiones.

OBJETIVE: To determine the influence of different factors involved in the decision to apply physical restraints (PR) in the management the elderly people with conduct disorders in an emergency department (ED) METHODS: A prospective observational study was conducted in the ED of the Hospital Universitario Severo Ochoa (Leganés, Madrid). We included 125 elderly people with disruptive behaviors and collected clinical, patient handling, organizational and environmental variables. Individuals who had undergone PR were analyzed to learn what factors were related to the final decision to restrain. RESULTS: 32.8% of the participants underwent PR. The aspects that most influenced the decision to restrain were those related to the organization and environment: specific staff training decreased the probability of restraint by 50% (P<.05) and good support from the whole team reduced the risk of using SF by up to 75% (P<.0005). Related patient handling factors such as verbal restraint, pain relief, family accompaniment and early mobilization significantly reduced the use of PR (P<.05). The only patient-dependent clinical aspect that increased the risk of SF was male sex (P<.05). Other factors unrelated to the probability of applying PR were, among others, nurse-patient ratio, type of behavior, age, or functional/cognitive status. CONCLUSIONS: Exclusively clinical factors of the patient had little influence on the decision to restrain the elderly in an ED. However, environmental, organizational, and behavioral handling variables could favor more respectful alternatives and thus reduce the use of PR in the elderly with disruptive behaviors in the ED.

Effectiveness of Treatment Approaches in COVID-19 Pneumonia: A Comparative Evaluation between a Specialized Center and Conventional Hospitals.

BACKGROUND: The early stages of the COVID-19 pandemic overwhelmed general hospitals in Spain. In response, a dedicated hospital for COVID-19 care, the Hospital de Emergencias Enfermera Isabel Zendal (HEEIZ), was established. This study aimed to compare clinical outcomes of COVID-19 patients treated at the specialized HEEIZ with those at conventional general hospitals (CGHs) in Madrid, Spain. METHODS: The study was a prospective, observational cohort study including COVID-19 patients admitted to the HEEIZ and 14 CGHs (December 2020 to August 2021). Patients were assigned based on hospital preference. Clinical data were collected and analyzed using multivariate regression to assess primary and secondary outcomes, including hospital mortality, need of invasive mechanical ventilation (IMV), and pharmacological treatments. RESULTS: The HEEIZ cohort (n = 2997) was younger and had lower Charlson comorbidity scores than the CGH cohort (n = 1526). Adjusted HEEIZ hospital mortality was not significantly higher compared with CGHs (OR: 1.274; 95% CI: 0.781-2.079; p = 0.332). CONCLUSIONS: During the study period, patients admitted to the HEEIZ showed no significant differences in clinical outcomes, compared with patients admitted at CGHs. These results might support the use of specialized centers in managing pandemic surges, allowing CGHs to handle other needs.

Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo.

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causal agent of Kaposi sarcoma, a cancer that appears as tumors on the skin or mucosal surfaces, as well as primary effusion lymphoma and KSHV-associated multicentric Castleman disease, which are B-cell lymphoproliferative disorders. Effective prophylactic and therapeutic strategies against KSHV infection and its associated diseases are needed. To develop these strategies, it is crucial to identify and target viral glycoproteins involved in KSHV infection of host cells. Multiple KSHV glycoproteins expressed on the viral envelope are thought to play a pivotal role in viral infection, but the infection mechanisms involving these glycoproteins remain largely unknown. We investigated the role of two KSHV envelope glycoproteins, KSHV complement control protein (KCP) and K8.1, in viral infection in various cell types in vitro and in vivo. Using our newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP, K8.1, or both, we demonstrated the presence of KCP and K8.1 on the surface of both virions and KSHV-infected cells. We showed that KSHV lacking KCP and/or K8.1 remained infectious in KSHV-susceptible cell lines, including epithelial, endothelial, and fibroblast, when compared to wild-type recombinant KSHV. We also provide the first evidence that KSHV lacking K8.1 or both KCP and K8.1 can infect human B cells in vivo in a humanized mouse model. Thus, these results suggest that neither KCP nor K8.1 is required for KSHV infection of various host cell types and that these glycoproteins do not determine KSHV cell tropism. IMPORTANCE: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human gamma-herpesvirus associated with the endothelial malignancy Kaposi sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. Determining how KSHV glycoproteins such as complement control protein (KCP) and K8.1 contribute to the establishment, persistence, and transmission of viral infection will be key for developing effective anti-viral vaccines and therapies to prevent and treat KSHV infection and KSHV-associated diseases. Using newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP and/or K8.1, we show that KCP and K8.1 can be found on the surface of both virions and KSHV-infected cells. Furthermore, we show that KSHV lacking KCP and/or K8.1 remains infectious to diverse cell types susceptible to KSHV in vitro and to human B cells in vivo in a humanized mouse model, thus providing evidence that these viral glycoproteins are not required for KSHV infection.

Targeting HER2/HER3 co-mutations in metastatic breast cancer: Case reports of exceptional responders to trastuzumab and pertuzumab therapy.

BACKGROUND: Overexpression of HER2 plays an important role in cancer progression and is the target of multiple therapies in HER2-positive breast cancer. Recent studies have also highlighted the presence of activating mutations in HER2, and HER3 that are predicted to enhance HER2 downstream pathway activation in a HER2-dependent manner. METHODS: In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab. RESULTS: Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2.

Association between occupational exposure and chronic obstructive pulmonary disease and respiratory symptoms in the Spanish population.

INTRODUCTION: The aim of this study was to analyze the impact of occupational exposure on chronic obstructive pulmonary disease (COPD) and respiratory symptoms in the general Spanish population. METHODS: This was a study nested in the Spanish EPISCAN II cross-sectional epidemiological study that included participants who had completed a structured questionnaire on their occupational history, a questionnaire on respiratory symptoms, and forced spirometry. The data were analyzed using Chi-square and Student's t tests and adjusted models of multiple linear regression and logistic regression. RESULTS: We studied 7502 subjects, 51.1% women, with a mean age of 60±11 years. Overall, 53.2% reported some respiratory symptoms, 7.9% had respiratory symptoms during their work activity, 54.2% were or had been smokers, and 11.3% (851 subjects) met COPD criteria on spirometry. A total of 3056 subjects (40.7%) reported exposure to vapors, gases, dust or fumes (VGDF); occupational exposure to VGDF was independently associated with the presence of COPD (OR 1.22, 95% CI: 1.03-1.44), respiratory symptoms (OR 1.45, 95%: CI 1.30-1.61), and respiratory symptoms at work (OR 4.69, 95% CI: 3.82-5.77), with a population attributable fraction for COPD of 8.2%. CONCLUSIONS: Occupational exposure is associated with a higher risk of COPD and respiratory symptoms in the Spanish population. These results highlight the need to follow strict prevention measures to protect the respiratory health of workers.

Association between occupational exposure and chronic obstructive pulmonary disease and respiratory symptoms in the Spanish population

Introduction: The aim of this study was to analyze the impact of occupational exposure on chronic obstructive pulmonary disease (COPD) and respiratory symptoms in the general Spanish population.MethodsThis was a study nested in the Spanish EPISCAN II cross-sectional epidemiological study that included participants who had completed a structured questionnaire on their occupational history, a questionnaire on respiratory symptoms, and forced spirometry. The data were analyzed using Chi-square and Student's t tests and adjusted models of multiple linear regression and logistic regression.ResultsWe studied 7502 subjects, 51.1% women, with a mean age of 60±11 years. Overall, 53.2% reported some respiratory symptoms, 7.9% had respiratory symptoms during their work activity, 54.2% were or had been smokers, and 11.3% (851 subjects) met COPD criteria on spirometry. A total of 3056 subjects (40.7%) reported exposure to vapors, gases, dust or fumes (VGDF); occupational exposure to VGDF was independently associated with the presence of COPD (OR 1.22, 95% CI: 1.03–1.44), respiratory symptoms (OR 1.45, 95%: CI 1.30–1.61), and respiratory symptoms at work (OR 4.69, 95% CI: 3.82–5.77), with a population attributable fraction for COPD of 8.2%.ConclusionsOccupational exposure is associated with a higher risk of COPD and respiratory symptoms in the Spanish population. These results highlight the need to follow strict prevention measures to protect the respiratory health of workers. (AU)

Parenteral Nutrition: Current Use, Complications, and Nutrition Delivery in Critically Ill Patients.

BACKGROUND: Parenteral nutrition (PN) is needed to avoid the development of malnutrition when enteral nutrition (EN) is not possible. Our main aim was to assess the current use, complications, and nutrition delivery associated with PN administration in adult critically ill patients, especially when used early and as the initial route. We also assessed the differences between patients who received only PN and those in whom EN was initiated after PN (PN-EN). METHODS: A multicenter (n = 37) prospective observational study was performed. Patient clinical characteristics, outcomes, and nutrition-related variables were recorded. Statistical differences between subgroups were analyzed accordingly. RESULTS: From the entire population (n = 629), 186 (29.6%) patients received PN as initial nutrition therapy. Of these, 74 patients (11.7%) also received EN during their ICU stay (i.e., PN-EN subgroup). PN was administered early (<48 h) in the majority of patients (75.3%; n = 140) and the mean caloric (19.94 ± 6.72 Kcal/kg/day) and protein (1.01 ± 0.41 g/kg/day) delivery was similar to other contemporary studies. PN showed similar nutritional delivery when compared with the enteral route. No significant complications were associated with the use of PN. Thirty-two patients (43.3%) presented with EN-related complications in the PN-EN subgroup but received a higher mean protein delivery (0.95 ± 0.43 vs 1.17 ± 0.36 g/kg/day; p = 0.03) compared with PN alone. Once adjusted for confounding factors, patients who received PN alone had a lower mean protein intake (hazard ratio (HR): 0.29; 95% confidence interval (CI): 0.18-0.47; p = 0.001), shorter ICU stay (HR: 0.96; 95% CI: 0.91-0.99; p = 0.008), and fewer days on mechanical ventilation (HR: 0.85; 95% CI: 0.81-0.89; p = 0.001) compared with the PN-EN subgroup. CONCLUSION: The parenteral route may be safe, even when administered early, and may provide adequate nutrition delivery. Additional EN, when possible, may optimize protein requirements, especially in more severe patients who received initial PN and are expected to have longer ICU stays. NCT Registry: 03634943.

GCN2 is required to maintain core body temperature in mice during acute cold.

Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress. Gcn2 deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose tissue (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly, Gcn2 deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose.NEW & NOTEWORTHY This paper details the discovery that GCN2 activation is required in both male and female mice to maintain core body temperature during acute cold exposure. The results point to a novel role for GCN2 in supporting adaptive thermogenesis via amino acid transport and actomyosin mechanics in brown adipose tissue.

Factors associated with the need of parenteral nutrition in critically ill patients after the initiation of enteral nutrition therapy.

Background and aims: Despite enteral nutrition (EN) is the preferred route of nutrition in patients with critical illness, EN is not always able to provide optimal nutrient provision and parenteral nutrition (PN) is needed. This is strongly associated with gastrointestinal (GI) complications, a feature of gastrointestinal dysfunction and disease severity. The aim of the present study was to investigate factors associated with the need of PN after start of EN, together with the use and complications associated with EN. Methods: Adult patients admitted to 38 Spanish intensive care units (ICUs) between April and July 2018, who needed EN therapy were included in a prospective observational study. The characteristics of EN-treated patients and those who required PN after start EN were analyzed (i.e., clinical, laboratory and scores). Results: Of a total of 443 patients, 43 (9.7%) received PN. One-third (29.3%) of patients presented GI complications, which were more frequent among those needing PN (26% vs. 60%, p = 0.001). No differences regarding mean energy and protein delivery were found between patients treated only with EN (n = 400) and those needing supplementary or total PN (n = 43). Abnormalities in lipid profile, blood proteins, and inflammatory markers, such as C-Reactive Protein, were shown in those patients needing PN. Sequential Organ Failure Assessment (SOFA) on ICU admission (Hazard ratio [HR]:1.161, 95% confidence interval [CI]:1.053-1.281, p = 0.003) and modified Nutrition Risk in Critically Ill (mNUTRIC) score (HR:1.311, 95% CI:1.098-1.565, p = 0.003) were higher among those who needed PN. In the multivariate analysis, higher SOFA score (HR:1.221, 95% CI:1.057-1.410, p = 0.007) and higher triglyceride levels on ICU admission (HR:1.004, 95% CI:1.001-1.007, p = 0.003) were associated with an increased risk for the need of PN, whereas higher albumin levels on ICU admission (HR:0.424, 95% CI:0.210-0.687, p = 0.016) was associated with lower need of PN. Conclusion: A higher SOFA and nutrition-related laboratory parameters on ICU admission may be associated with the need of PN after starting EN therapy. This may be related with a higher occurrence of GI complications, a feature of GI dysfunction. Clinical trial registration: ClinicalTrials.gov: NCT03634943.

Hybrid approach for solving real-world bin packing problem instances using quantum annealers.

Efficient packing of items into bins is a common daily task. Known as Bin Packing Problem, it has been intensively studied in the field of artificial intelligence, thanks to the wide interest from industry and logistics. Since decades, many variants have been proposed, with the three-dimensional Bin Packing Problem as the closest one to real-world use cases. We introduce a hybrid quantum-classical framework for solving real-world three-dimensional Bin Packing Problems (Q4RealBPP), considering different realistic characteristics, such as1) package and bin dimensions, (2) overweight restrictions, (3) affinities among item categories and (4) preferences for item ordering. Q4RealBPP permits the solving of real-world oriented instances of 3 dBPP, contemplating restrictions well appreciated by industrial and logistics sectors.

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel.

BACKGROUND: A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors. METHODS: 10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m2 plus nab paclitaxel 220 mg/m2 every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response. RESULTS: With cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase ß, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue. CONCLUSIONS: Priming patients' chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses. TRIAL REGISTRATION: This clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853.

Benchmark dataset and instance generator for real-world three-dimensional bin packing problems.

In this article, a benchmark for real-world bin packing problems is proposed. This dataset consists of 12 instances of varying levels of complexity regarding size (with the number of packages ranging from 38 to 53) and user-defined requirements. In fact, several real-world-oriented restrictions were taken into account to build these instances: i) item and bin dimensions, ii) weight restrictions, iii) affinities among package categories iv) preferences for package ordering and v) load balancing. Besides the data, we also offer an own developed Python script for the dataset generation, coined Q4RealBPP-DataGen. The benchmark was initially proposed to evaluate the performance of quantum solvers. Therefore, the characteristics of this set of instances were designed according to the current limitations of quantum devices. Additionally, the dataset generator is included to allow the construction of general-purpose benchmarks. The data introduced in this article provides a baseline that will encourage quantum computing researchers to work on real-world bin packing problems.

Microbiota Mediate Enhanced Exercise Capacity Induced by Exercise Training.

PURPOSE: We investigated the effects of gut microbes, and the mechanisms mediating the enhanced exercise performance induced by exercise training, i.e., skeletal muscle blood flow, and mitochondrial biogenesis and oxidative function in male mice. METHODS: All mice received a graded exercise test before (PRE) and after exercise training via forced treadmill running at 60% to 70% of maximal running capacity 5 d·wk -1 for 5 wk (POST). To examine the role of the gut microbes, the graded exercise was repeated after 7 d of access to antibiotic (ABX)-treated water, used to eliminate gut microbes. Peripheral blood flow, mitochondrial oxidative capacity, and markers of mitochondrial biogenesis were collected at each time point. RESULTS: Exercise training led to increases of 60% ± 13% in maximal running distance and 63% ± 11% work to exhaustion ( P < 0.001). These increases were abolished after ABX ( P < 0.001). Exercise training increased hindlimb blood flow and markers of mitochondrial biogenesis and oxidative function, including AMP-activated protein kinase, sirtuin-1, PGC-1α citrate synthase, complex IV, and nitric oxide, all of which were also abolished by ABX treatment. CONCLUSIONS: Our results support the concept that gut microbiota mediate enhanced exercise capacity after exercise training and the mechanisms responsible, i.e., hindlimb blood flow, mitochondrial biogenesis, and metabolic profile. Finally, results of this study emphasize the need to fully examine the impact of prescribing ABX to athletes during their training regimens and how this may affect their performance.

Promotion of physical activity after hospitalization for COPD exacerbation: A randomized control trial.

BACKGROUND AND OBJECTIVE: Physical activity worsens during exacerbations of chronic obstructive pulmonary disease (COPD) and notably after hospitalizations. Pedometer-based interventions are useful to increase physical activity in stable patients with COPD. However, there is little information concerning the implementation of such programs following severe exacerbation. This study assessed the efficacy of a physical activity program after hospitalization for a COPD exacerbation. METHODS: We performed a prospective, 12-week, parallel group, assessor-blinded, randomized control trial in COPD patients hospitalized for an exacerbation. After discharge, physical activity and other secondary variables were assessed. Patients were allocated (1:1) to a physical activity promotion program (intervention group, IG) or usual care (control group, CG). Based on a motivational interview and accelerometer physical activity assessment, a patient-tailored, pedometer-based, progressive and target-driven program was designed. Linear mixed effect models were used to analyse between-group differences. RESULTS: Forty-six out of 61 patients recruited were randomized and 43 (IG = 20, CG = 23) completed the study. In-hospital and baseline characteristics were similar in both groups. After 12 weeks of intervention, the mean steps difference between groups was 2093 steps/day, p = 0.018, 95% CI 376-4012, favouring the IG. Only the IG significantly increased the number of steps/day compared to baseline (mean difference [95% CI] 2932 [1069-4795] steps; p = 0.004). There were no other between-group differences. CONCLUSION: After hospitalization for a COPD exacerbation, a patient-tailored physical activity program based on a motivational interview and the use of pedometers, with progressive and customized targets, improved the number of steps/day.

Evolution of nutrition support in patients with COVID-19 disease admitted in the Intensive Care Unit.

INTRODUCTION: Nutritional support in patients with COVID19 can influence the mean stay and complications in the patient in Intensive Care Unit (ICU). AIMS: To evaluate the selection of enteral nutritional treatment in the COVID-19 patient admitted to the ICU. To know the development of dysphagia and its treatment. To evaluate the adjustment to the requirements and its relationship with the patient's complications. MATERIAL AND METHODS: One-center longitudinal retrospective study in 71 patients admitted to the ICU with COVID19 infection and complete enteral nutrition between March and April 2020. Clinical variables were collected: length of stay in ICU, mean stay and rate of complications; and estimated anthropometric variables. RESULTS: The mean age was 61.84 (13.68) years. Among the patients analyzed, 33 (46.5%) died. The median stay in the ICU was 20 (15.75-32) days and the mean stay was 37 (26.75-63) days. The type of formula most prescribed was normoprotein 24 (35.3%) and diabetes-specific 23 (33.8%) depending on the prescribed formula. There was no difference in mean stay (p = 0.39) or death rate (p = 0.35). The percentage of achievement of the estimated protein requirements was 50 (34.38-68.76). At discharge, 8 (21%) of the patients had dysphagia. A relationship was observed between the mean ICU stay and the probability of developing dysphagia (OR: 1.035 (1.004-1.07); p = 0.02). CONCLUSIONS: In the patient with COVID19 disease admitted to the ICU, only half of the necessary protein requirements were reached. The presence of dysphagia at discharge was related to the length of time the patient was in the ICU.

Digital Quantum Simulation and Circuit Learning for the Generation of Coherent States.

Coherent states, known as displaced vacuum states, play an important role in quantum information processing, quantum machine learning, and quantum optics. In this article, two ways to digitally prepare coherent states in quantum circuits are introduced. First, we construct the displacement operator by decomposing it into Pauli matrices via ladder operators, i.e., creation and annihilation operators. The high fidelity of the digitally generated coherent states is verified compared with the Poissonian distribution in Fock space. Secondly, by using Variational Quantum Algorithms, we choose different ansatzes to generate coherent states. The quantum resources-such as numbers of quantum gates, layers and iterations-are analyzed for quantum circuit learning. The simulation results show that quantum circuit learning can provide high fidelity on learning coherent states by choosing appropriate ansatzes.

Pneumococcal meningitis secondary to otitis media in two patients with COVID-19 omicron variant.

BACKGROUND: The SARS-CoV-2 omicron variant produces more symptoms in the upper respiratory tract than in the lower respiratory tract. This form of "common cold" can cause inflammation of the oropharynx and the Eustachian tube, leading to the multiplication of bacteria such as Streptococcus pneumoniae in the oropharynx. Eustachian tube dysfunction facilitates migration of these bacteria to the middle ear, causing inflammation and infection (otitis media), which in turn could lead to further complications such as acute mastoiditis and meningitis. CASE PRESENTATION: In January 2022, during the rapid spread of the omicron variant of the SARS-CoV-2 virus, two patients presented to the emergency room at our hospital complaining of headache and a low level of consciousness. A few days prior to admission, the patients had been diagnosed with COVID-19 based on clinical manifestations of a cold virus, without respiratory failure. Cranial computed tomography revealed signs of bilateral invasion of the middle ear in both cases. Lumbar puncture was compatible with acute bacterial meningitis, and S. pneumoniae was isolated in cerebrospinal fluid in both patients. RT-PCR tests for SARS-CoV-2 were repeated, confirming the presence of the omicron variant in one of the patients. We were unable to confirm the variant in the second patient due to the low viral load in the nasopharyngeal sample obtained at admission. However, the time of diagnosis (i.e., during the peak spread of the omicron variant), strongly suggest the presence of the omicron variant. Both patients were admitted to the intensive care unit and both showed rapid clinical improvement after initiation of antibiotic treatment. CONCLUSIONS: The omicron variant of the SARS-CoV-2 virus can promote the development of otitis media and secondary acute bacterial meningitis. S. pneumoniae is one of the main bacteria involved in this process.

Recomendaciones para el manejo de la hiperpotasemia en urgencias / Recommendations for the management of hyperkalemia in the emergency department

La hiperpotasemia es un trastorno electrolítico frecuente en los servicios de urgencias y un manejo adecuado impacta en el pronóstico de los pacientes. Este requiere de la integración de datos clínicos y analíticos sobre el estado de la función renal, la hidratación, el equilibrio ácido-base y la afectación cardiaca. Además, es necesaria una precisa toma de decisiones sobre la corrección de la concentración de potasio en el tiempo indicado para cada caso. Por estos mo- tivos la SEMES (Sociedad Española de Medicina de Urgencias y Emergencias), la SEC (Sociedad Española de Cardiología) y la SEN (Sociedad Española de Nefrología) unen esfuerzos en consensuar definiciones y tratamientos que podrían mejorar el abordaje de estos pacientes en los servicios de urgencias hospitalarios. El calcio intravenoso, la insulina con glucosa y el salbutamol siguen siendo los tratamientos que se emplean en la hiperpotasemia aguda. Los diuréticos de asa y tiazídicos también pueden ayudar en pacientes no depleccionados, y la hemodiálisis puede ser necesaria en hiperpotasemias graves en el contexto de insuficiencia renal. Los efectos secundarios y la baja tolerabilidad de las resinas de intercambio iónico están haciendo que caigan en desuso mientras que los nuevos intercambiadores catiónicos gastrointestinales van ganando su espacio e incluso podrían tener algún valor en el tratamiento agudo. Es fundamental el ajuste del tratamiento evitando retirar fármacos que, a pesar de favorecer la hiperpotasemia, mejoren el pronóstico a largo plazo, por lo que es imperativo buscar alternativas válidas para cada grupo de pacientes, asegurando después un estrecho seguimiento. (AU)

Hyperkalemia, a common electrolyte disorder, is seen often in emergency departments. Patient outcomes are impacted by proper management, which requires consideration of both clinical and laboratory findings in relation to kidney function, hydration, the acid–base balance, and heart involvement. Delicate decisions about the timing of potassium level correction must be tailored in each case. For these reasons the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Nephrology (SEN) joined forces to come to a consensus on defining the problem and recommending treatments that improve hospital emergency department management of hyperkalemia. Intravenous calcium, insulin and glucose, and salbutamol continue to be used to treat acute hyperkalemia. Either loop or thiazide diuretics can help patients if volume is not depleted, and dialysis may be necessary if there is kidney failure. Ion-exchange resins are falling into disuse because of adverse effects and poor tolerance, whereas novel gastrointestinal cation-exchange resins are gaining ground and may even be of some use in managing acute cases. It is essential to adjust treatment rather than discontinue medications that, even if they favor the development of hyperkalemia, will improve a patient’s long-term prognosis. Valid alternative treatment approaches must therefore be sought for each patient group, and close follow-up is imperative. (AU)

Recommendations for the management of hyperkalemia in the emergency department. / Recomendaciones para el manejo de la hiperpotasemia en urgencias.

TEXT: Hyperkalemia, a common electrolyte disorder, is seen often in emergency departments. Patient outcomes are impacted by proper management, which requires consideration of both clinical and laboratory findings in relation to kidney function, hydration, the acid-base balance, and heart involvement. Delicate decisions about the timing of potassium level correction must be tailored in each case. For these reasons the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Nephrology (SEN) joined forces to come to a consensus on defining the problem and recommending treatments that improve hospital emergency department management of hyperkalemia. Intravenous calcium, insulin and glucose, and salbutamol continue to be used to treat acute hyperkalemia. Either loop or thiazide diuretics can help patients if volume is not depleted, and dialysis may be necessary if there is kidney failure. Ion-exchange resins are falling into disuse because of adverse effects and poor tolerance, whereas novel gastrointestinal cation-exchange resins are gaining ground and may even be of some use in managing acute cases. It is essential to adjust treatment rather than discontinue medications that, even if they favor the development of hyperkalemia, will improve a patient's long-term prognosis. Valid alternative treatment approaches must therefore be sought for each patient group, and close follow-up is imperative.

TEXTO: La hiperpotasemia es un trastorno electrolítico frecuente en los servicios de urgencias y un manejo adecuado impacta en el pronóstico de los pacientes. Este requiere de la integración de datos clínicos y analíticos sobre el estado de la función renal, la hidratación, el equilibrio ácido-base y la afectación cardiaca. Además, es necesaria una precisa toma de decisiones sobre la corrección de la concentración de potasio en el tiempo indicado para cada caso. Por estos motivos la SEMES (Sociedad Española de Medicina de Urgencias y Emergencias), la SEC (Sociedad Española de Cardiología) y la SEN (Sociedad Española de Nefrología) unen esfuerzos en consensuar definiciones y tratamientos que podrían mejorar el abordaje de estos pacientes en los servicios de urgencias hospitalarios. El calcio intravenoso, la insulina con glucosa y el salbutamol siguen siendo los tratamientos que se emplean en la hiperpotasemia aguda. Los diuréticos de asa y tiazídicos también pueden ayudar en pacientes no depleccionados, y la hemodiálisis puede ser necesaria en hiperpotasemias graves en el contexto de insuficiencia renal. Los efectos secundarios y la baja tolerabilidad de las resinas de intercambio iónico están haciendo que caigan en desuso mientras que los nuevos intercambiadores catiónicos gastrointestinales van ganando su espacio e incluso podrían tener algún valor en el tratamiento agudo. Es fundamental el ajuste del tratamiento evitando retirar fármacos que, a pesar de favorecer la hiperpotasemia, mejoren el pronóstico a largo plazo, por lo que es imperativo buscar alternativas válidas para cada grupo de pacientes, asegurando después un estrecho seguimiento.