Novel insights into Antithrombin Deficiency enabled by Mass Spectrometry-based Precision Diagnostics.

BACKGROUND: Although P5 (preventive, personalized, predictive, participatory, psychocognitive) medicine and patient focused healthcare are gaining ground in various healthcare areas, the diagnosis of antithrombin deficiency (ATD) is still based on crude diagnostic tests clustering patients into clinically heterogeneous subgroups whereby relevant thrombophilia phenotypes may go unnoticed. Clinical pathways and the majority of evidence are based on these tests, therefore generic treatment is still the norm. OBJECTIVES: To unravel the heterogeneity of ATD, a mass spectrometry (LC-MRM-MS)-based test for antithrombin was developed allowing molecular characterization of the antithrombin proteoforms in patient plasma. This study provides the first insight into the tests' clinical performance. METHODS: Plasma from 91 unrelated ATD patients and 41 patients with a congenital disorder of glycosylation affecting antithrombin glycosylation were characterized functionally, genetically, and analyzed by LC-MRM-MS. An established data analysis strategy was applied for quantitation and molecular characterization of antithrombin proteoforms. RESULTS: The test recognized patients with a quantitative defect, discriminated between type I and type II ATD, and identified variant proteoforms. Overall, the diagnostic sensitivity for ATD was 100% for LC-MRM-MS compared to 81.1% by the functional test. Type II ATD, a subtype prone to misdiagnosis, revealed an even larger difference of 100% identification by LC-MRM-MS versus 56.8% by functional test. CONCLUSIONS: The qualitative and quantitative MS-based AT-test can serve as a platform for investigating the molecular basis of the clinical heterogeneity of ATD. This Precision Diagnostics approach for ATD can lower diagnostic uncertainty and modernize the ATD diagnostic and clinical pathways.

Fluid bolus resuscitation with hypertonic saline albumin solution in critically ill children: a prospective observational pilot study.

To evaluate the hemodynamic effects and the safety profile of fluid bolus resuscitation with hypertonic saline albumin (HSA) in critically ill children, we performed a prospective observational pilot study between October 2018 and May 2021 in the pediatric intensive care unit (PICU) in a tertiary hospital in Madrid, Spain. Sixty-four HSA boluses were analyzed in 23 patients. A mean volume of 5.7 ml/kg (Standard Deviation, SD 2.3 ml/kg) per bolus was infused. Acute hypotension was the main indication. 91% of the patients had a cardiac disease, 56% of them had undergone cardiac surgery in the previous 72 h, and 47.8% associated right ventricular dysfunction. A significant increase in systolic, mean, and diastolic blood pressure and a decrease in the vasoactive index was observed after the infusion of HSA. This effect lasted for twenty-four hours (p < 0.05). Moreover, the amount of fluid requirements decreased significantly in the 6 h following HSA infusion [8.7 ml/kg (SD 9.6) vs. 15.1 ml/kg (SD 13.6) in the previous 6 h (p < 0.05)]. Serum levels of sodium and chloride increased after the infusion, reaching their peak concentration after one hour (143 mEq/L (SD 3.5) and 109.7 mEq/L (SD 6) respectively). HSA-related metabolic acidosis or acute kidney injury were not observed in this study. Hypertonic saline albumin is safe and effective when infused at a dose of 5 ml/kg in critically ill children. However, further research is required to confirm our findings.

Reduced Plasma Selenoprotein P Is Associated With Type I Antithrombin Deficiency and a Prothrombotic State.

CONTEXT.­: A positive association between antithrombin activity and selenium level was reported. Selenoprotein P, the most important selenium carrier, was identified within human plasma fibrin clots. OBJECTIVE.­: To investigate the relationship between selenoprotein P and antithrombin and its role in modulation of fibrin clot properties in antithrombin-deficient patients. DESIGN.­: Proteomic analysis of plasma fibrin clots was performed with mass spectrometry. In 108 patients with genetically confirmed type I (57%) or type II (43%) antithrombin deficiency and in healthy controls (n = 50), we assessed plasma selenoprotein P levels and thiobarbituric acid-reactive substances by enzyme-linked immunosorbent assay, along with fibrin clot permeability, clot lysis time, and thrombin generation. RESULTS.­: Clot-bound antithrombin concentration was 0.46 ± 0.32 mg/g protein, while selenoprotein P level was 30-fold lower (0.015 ± 0.012 mg/g). Type I compared to type II antithrombin-deficient patients had higher clot-bound antithrombin and selenoprotein P levels (both P < .001), associated together (ρ = 0.93, P < .001). Individuals with type I compared to type II antithrombin deficiency or controls had about 40% lower plasma selenoprotein P levels (P < .001). In antithrombin-deficient patients, plasma selenoprotein P was associated with antithrombin antigen (ρ = 0.35, P < .001) and thiobarbituric acid-reactive substances (ρ = 0.42, P < .001). Plasma selenoprotein P correlated also with endogenous thrombin potential (r = -0.33, P < .001), fibrin clot permeability (r = 0.43, P < .001), and clot lysis time (r = -0.40, P < .001) in antithrombin-deficient patients but not in controls. CONCLUSIONS.­: Patients with type I antithrombin deficiency had higher clot-bound selenoprotein P and reduced plasma selenoprotein P levels. Plasma selenoprotein P was associated with prothrombotic fibrin clot phenotype and enhanced thrombin generation.

Genomically-supported Redefinition of an Outbreak in a Pediatric Unit Caused by blaVIM -harboring Klebsiella michiganensis.

BACKGROUND: Klebsiella michiganensis , a member of the Klebsiella oxytoca complex, is an emerging nosocomial pathogen known to frequently carry plasmids with antibiotic-resistance genes, including carbapenemases. Using genomics, this study redefined an outbreak alert of K. michiganensis carrying a blaVIM carbapenemase in a pediatric ward in a Spanish hospital. METHODS: A total of 31 isolates of Verona integron-encoded metallo-ß-lactamase (VIM)-carbapenemase K. oxytoca from suspected outbreak cases and unrelated controls from 2015 to 2022 were analyzed. Whole-genome sequencing (both short and long reads) was applied to determine phylogenetic relationships based on single-nucleotide polymorphisms (SNPs) and identify plasmids and antimicrobial resistance genes. RESULTS: The sequences from 12 isolates identified in 2021 showed pairwise SNP distances ranging from 0 to 16 SNPs, confirming the outbreak. Examination of isolates before and after the study period revealed 7 additional cases, 2 in 2020 and 5 in 2022. The outbreak comprised 18 isolates from 17 patients in 3 different pediatric wards, together with 1 environmental sample. In all outbreak isolates, the blaVIM-1 gene was located within a gene cassette carried by a class 1 integron on an IncFIB(pQil) plasmid. A genomic network based on SNPs revealed 5 unsampled intermediate nodes, suggesting additional subclones that may have involved healthcare staff, patient relatives or environmental reservoirs. Blood and rectal isolates obtained from the same patient were positioned on separate branches of the network, making a direct evolutionary pathway between them unlikely. CONCLUSIONS: Our study redefined the full extent of this K. michiganensis -VIM outbreak and highlights the critical importance of genomic analysis in accurately understanding outbreaks in healthcare settings.

Development of the Interosseous Muscles of the Human Hand: Morphological and Functional Aspects of the Terminal Insertion.

INTRODUCTION: To date, there have been no studies conducted on the development of interosseous muscles (IO) in the human hand. This study aimed to investigate the development of these muscles in order to clarify their terminal insertions and their relationship with the metacarpophalangeal joints. METHODS: Serial sections of 25 human specimens (9 embryos and 16 fetuses) between the 7th and 14th weeks of development, sourced from the Collection of the Department of Anatomy and Embryology at UCM Faculty of Medicine, were analyzed bilaterally using a conventional optical microscope. RESULTS: Our findings revealed that, during the 7th week of development, the metacarpophalangeal interzone mesenchyme extended into the extensor apparatus of the fingers. Furthermore, we observed that the joint capsule and the tendon of the IO derive from the articular interzone mesenchyme. By the end of the 7th week, corresponding to Carnegie stage 21, the myotendinous junction appeared, initiating cavitation of the metacarpophalangeal joint. During the fetal period, the terminal insertions of the IO were identified: both the dorsal interosseous (DI) and palmar interosseous (PI) muscles insert into the metacarpophalangeal joint capsule and establish a connection with the volar plate located at the base of the proximal phalanx and the extensor apparatus. Some muscle fibers also attach to the joint capsule at the level of the proximal synovial cul-de-sac. The functional implications of these findings are discussed within this work. CONCLUSION: This study provides the first detailed description of the development of the interosseous muscles in the human hand.

Low-to-moderate alcohol consumption is associated with increased fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: Both metabolic dysfunction and alcohol consumption cause steatotic liver disease (SLD). The distinction between metabolic dysfunction-associated SLD (MASLD) and MetALD categories is based on arbitrary thresholds of alcohol intake. Thus, we assessed the impact of different levels of alcohol consumption on SLD severity and their interaction with metabolic comorbidities. METHODS: We performed a population-based study with transient elastography (FibroScan®) data from participants in Spain (derivation cohort) and the US (validation cohort). A controlled attenuation parameter ≥275 dB/m was used to define SLD. At least one cardiometabolic risk factor was required to define MASLD. Among patients with MASLD, low alcohol consumption was defined as an average of 5-9 drinks/week, moderate consumption as 10-13 drinks/week for females and 10-20 drinks/week for males, and increased alcohol intake (MetALD) as 14-35 drinks/week for females and 21-42 drinks/week for males. Significant fibrosis was defined as a liver stiffness measurement ≥8 kPa and at-risk metabolic dysfunction-associated steatohepatitis (MASH) as a FAST score ≥0.35. RESULTS: The derivation cohort included 2,227 individuals with MASLD (9% reported low, 14% moderate alcohol consumption) and 76 cases with MetALD. Overall prevalences of significant fibrosis and at-risk MASH were 7.6% and 14.8%, respectively. In the multivariable analysis, alcohol consumption was independently associated with significant fibrosis and at-risk MASH. A dose-dependent increase in the prevalence of significant fibrosis and at-risk MASH was observed between the number of drinks/week and the number of cardiometabolic factors. The validation cohort included 1,732 participants with MASLD, of whom 17% had significant fibrosis and 13% at-risk MASH. This cohort validated the association between moderate intake and MASLD at risk of progression (odds ratio 1.69, 95% CI 1.06-2.71). CONCLUSIONS: Moderate alcohol intake is commonly seen in MASLD and increases the risk of advanced disease to a level similar to that observed in MetALD. IMPACT AND IMPLICATIONS: Metabolic risk factors such as overweight, diabetes or dyslipidemia, and alcohol consumption can cause liver disease. These factors frequently coexist, but their joint effects on liver fibrosis remain uncertain. In this study, we have analyzed individuals from the general population with MASLD (metabolic dysfunction-associated steatotic liver disease) enrolled in Spain and the US. We show that moderate alcohol consumption has a supra-additive effect with metabolic risk factors, exponentially increasing the risk of liver fibrosis. These results suggest that there are no safe limits of daily alcohol intake in patients with unhealthy metabolic status and MASLD.

Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins.

Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules.

Consensus document of the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Intensive Care (SECIP) for the diagnosis and treatment of central venous catheter-related infections in paediatric care.

Intravascular devices are essential for the diagnostic and therapeutic approach to multiple diseases in paediatrics, and central venous catheters (CVCs) are especially important. One of the most frequent complications is the infection of these devices, which is associated with a high morbidity and mortality. These infections are highly complex, requiring the use of substantial resources, both for their diagnosis and treatment, and affect vulnerable paediatric patients admitted to high-complexity units more frequently. There is less evidence on their management in paediatric patients compared to adults, and no consensus documents on the subject have been published in Spain. The objective of this document, developed jointly by the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Intensive Care (SECIP), is to provide consensus recommendations based on the greatest degree of evidence available to optimize the diagnosis and treatment of catheter-related bloodstream infections (CRBSIs). This document focuses on non-neonatal paediatric patients with CRBSIs and does not address the prevention of these infections.

Thrombotic risk and features of patients with inferior vena cava agenesis: a multicentre, retrospective, observational study.

BACKGROUND: Inferior vena cava agenesis (IVCA) is a rare anomaly predisposing affected people to lower-limb venous thrombosis with low frequency of pulmonary embolism. Antenatal thrombosis and inherited thrombophilia have been suggested as causes of IVCA. However, there is little evidence on the clinical course and management of this condition. We designed a patient registry to assess the thrombotic risk and features of IVCA. METHODS: In this this multicentre, retrospective, observational study, we included patients with IVCA diagnosed by routine imaging from 20 hospitals in Spain (n=18), Portugal (n=1), and Italy (n=1). Patients were identified from a systematic search in radiology databases using data extraction software (cohort A) and alternative searches in medical records for confirmed IVCA (cohort B; option allowed when systematic approaches were unapplicable). Primary outcomes were clinical and imaging features, thrombotic risk, phenotype of IVCA-associated thrombosis, anticoagulant treatment, and the results of thrombophilia testing. FINDINGS: We included patients with IVCA diagnosed by routine imaging studies done between Jan 1, 2010, and Dec 31, 2022. In the systematic search, 4 341 333 imaging exams were screened from the radiology databases of eight centres. 122 eligible patients were enrolled in cohort A. A further 95 patients were identified by screening medical records at 12 centres, of whom 88 were eligible and included in cohort B, making a combined cohort of 210 patients. 96 (46%) of 210 patients were female and 200 (95%) were European or Hispanic. 60 (29%) of 210 patients had hepatic IVC interruption, whereas 150 (71%) had extrahepatic IVCA. In cohort A, 65 (53%) of 122 patients had venous thrombosis, with an estimated annual risk of 1·15% (95% CI 0·89-1·46). Extrahepatic IVCA was associated with a greater risk of venous thrombosis than hepatic IVCA (56 [67%] of 84 patients vs nine [24%] of 38 patients, odds ratio 5·31, 95% CI 2·27-12·43; p<0·0001). Analysis of 126 patients with venous thrombosis pooled from cohorts A and B showed early-onset (median age 34·6 years, IQR 23·3-54·3) and recurrent events (50 [40%] of 126 patients). Patients with extrahepatic IVCA had greater proportions of lower-limb venous thrombosis (95 [87%] of 109 vs nine [53%] of 17, p=0·0010) and recurrence (48 [44%] of 109 vs two [12%] of 17, p=0·015), but lower rates of pulmonary embolism (10 [10%] of 99 vs four [33%] of 12, p=0·044) than did patients with hepatic IVCA. 77 (63%) of 122 patients with thrombosis underwent indefinite anticoagulation. 32 (29%) of 111 patients (29 [34%] of 86 with thrombosis) had coexisting thrombophilias. The recurrence risk was lower for patients receiving indefinite anticoagulation (adjusted odds ratio 0·24, 95% CI 0·08-0·61; p=0·010), and greater for thrombophilias (3·19, 1·09-9·32; p=0·034). INTERPRETATION: This evaluation of a large patient cohort demonstrates the high thrombotic burden of IVCA. We have identified two distinct forms of IVCA, hepatic and extrahepatic, suggesting different underlying mechanisms. Beyond clinical characterisation, we draw attention to this orphan disease and highlight the need for its study and improved care. FUNDING: Spanish Society of Thrombosis and Haemostasis, Instituto de Salud Carlos III, FEDER, Fundación Séneca.

Colossal Reversible Barocaloric Effects in a Plastic Crystal Mediated by Lattice Vibrations and Ion Diffusion.

Solid-state methods for cooling and heating promise a sustainable alternative to current compression cycles of greenhouse gases and inefficient fuel-burning heaters. Barocaloric effects (BCE) driven by hydrostatic pressure (p) are especially encouraging in terms of large adiabatic temperature changes (|ΔT| ≈ 10 K) and isothermal entropy changes (|ΔS| ≈ 100 J K-1 kg-1). However, BCE typically require large pressure shifts due to irreversibility issues, and sizeable |ΔT| and |ΔS| seldom are realized in a same material. Here, the existence of colossal and reversible BCE in LiCB11H12 is demonstrated near its order-disorder phase transition at ≈380 K. Specifically, for Δp ≈ 0.23 (0.10) GPa, |ΔSrev| = 280 (200) J K-1 kg-1 and |ΔTrev| = 32 (10) K are measured, which individually rival with state-of-the-art BCE figures. Furthermore, pressure shifts of the order of 0.1 GPa yield huge reversible barocaloric strengths of ≈2 J K-1 kg-1 MPa-1. Molecular dynamics simulations are performed to quantify the role of lattice vibrations, molecular reorientations, and ion diffusion on the disclosed BCE. Interestingly, lattice vibrations are found to contribute the most to |ΔS| while the diffusion of lithium ions, despite adding up only slightly to the entropy change, is crucial in enabling the molecular order-disorder phase transition.

Vaccimel immunization is associated with enhanced response to treatment with anti-PD-1 monoclonal antibodies in cutaneous melanoma patients - a case reports study.

Cancer vaccines are gaining ground as immunotherapy options. We have previously demonstrated in cutaneous melanoma (CM) patients that adjuvant treatment with VACCIMEL, a mixture of four irradiated CM cell lines co-adjuvanted with BCG and GM-CSF, increases the cellular immune response to melanocyte differentiation antigens, cancer-testis antigens and neoantigens, with respect to basal levels. On the other hand, it is also known that treatment with anti-PD-1 monoclonal antibodies (MAbs), acting on pre-existing tumor-reactive lymphocytes, induces clinical responses in CM patients, albeit in a fraction of treated patients. A combination of both treatments would appear therefore desirable. In this paper, we describe CM patients who, having progressed even years after vaccination, were treated with anti-PD-1 MAbs. In 5/5 of such progressor patients, complete responses were obtained which lasted between 3 and 65+ months. Three of the patients remain disease-free and two recurred. One of the patients passed away after a recurrence of brain metastases. We suggest that clonally expanded reactive lymphocytes induced by VACCIMEL partially remain as memory cells, which may be recalled after tumor recurrence and may foster ulterior activity of anti-PD-1 MAbs.

Outcomes associated with ventilator-associated events (VAE), respiratory infections (VARI), pneumonia (VAP) and tracheobronchitis (VAT) in ventilated pediatric ICU patients: A multicentre prospective cohort study.

OBJECTIVES: An objective categorization of respiratory infections based on outcomes is an unmet clinical need. Ventilator-associated pneumonia and tracheobronchitis remain used in clinical practice, whereas ventilator-associated events (VAE) are limited to surveillance purposes. RESEARCH METHODOLOGY/DESIGN: This was a secondary analysis from a multicentre observational prospective cohort study. VAE were defined as a sustained increase in minimum Oxygen inspired fraction (FiO2) and/or Positive end-expiratory pressures (PEEP) of ≥ 0.2/2 cm H2O respectively, or an increase of 0.15 FiO2 + 1 cm H20 positive end-expiratory pressures for ≥ 1 calendar-day. SETTING: 15 Paediatric Intensive Care Units. MAIN OUTCOME MEASURES: Mechanical ventilation duration, intensive care and hospital length of stay; (LOS) and mortality. RESULTS: A cohort of 391 ventilated children with an age (median, [Interquartile Ranges]) of 1 year[0.2-5.3] and 7 days[5-10] of mechanical ventilation were included. Intensive care and hospital stays were 11 [7-19] and 21 [14-39] days, respectively. Mortality was 5.9 %. Fifty-eight ventilator-associated respiratory infections were documented among 57 patients: Seventeen (29.3 %) qualified as ventilator-associated pneumonia (VAP) and 41 (70.7 %) as ventilator-associated tracheobronchitis (VAT). Eight pneumonias and 16 tracheobronchitis (47 % vs 39 %,P = 0.571) required positive end-expiratory pressure or oxygen increases consistent with ventilator-associated criteria. Pneumonias did not significantly impact on outcomes when compared to tracheobronchitis. In contrast, infections (pneumonia or tracheobronchitis) following VAEs criteria were associated with > 6, 8 and 15 extra-days of ventilation (16 vs 9.5, P = 0.001), intensive care stay (23.5 vs 15; P = 0.004) and hospital stay (39 vs 24; P = 0.015), respectively. CONCLUSION: When assessing ventilated children with respiratory infections, VAE apparently is associated with higher ventilator-dependency and LOS compared with pneumonia or tracheobronchitis. IMPLICATIONS FOR PRACTICE: Incorporating the modification of ventilatory settings for further categorization of the respiratory infections may facilitate therapeutic management among ventilated patients.

Targeted long-read sequencing identifies and characterizes structural variants in cases of inherited platelet disorders.

BACKGROUND: Genetic diagnosis of inherited platelet disorders (IPDs) is mainly performed by high-throughput sequencing (HTS). These short-read-based sequencing methods sometimes fail to characterize the genetics of the disease. OBJECTIVES: To evaluate nanopore long-read DNA sequencing for characterization of structural variants (SVs) in patients with IPDs. METHODS: Four patients with a clinical and laboratory diagnosis of Glanzmann thrombasthenia (GT) (P1 and P2) and Hermansky-Pudlak syndrome (HPS) (P3 and P4) in whom HTS missed the underlying molecular cause were included. DNA was analyzed by both standard HTS and nanopore sequencing on a MinION device (Oxford Nanopore Technologies) after enrichment of DNA spanning regions covering GT and HPS genes. RESULTS: In patients with GT, HTS identified only 1 heterozygous ITGB3 splice variant c.2301+1G>C in P2. In patients with HPS, a homozygous deletion in HPS5 was suspected in P3, and 2 heterozygous HPS3 variants, c.2464C>T (p.Arg822∗) and a deletion affecting 2 exons, were reported in P4. Nanopore sequencing revealed a complex SV affecting exons 2 to 6 in ITGB3 (deletion-inversion-duplication) in homozygosity in P1 and compound heterozygosity with the splice variant in P2. In the 2 patients with HPS, nanopore defined the length of the SVs, which were characterized at nucleotide resolution. This allowed the identification of repetitive Alu elements at the breakpoints and the design of specific polymerase chain reactions for family screening. CONCLUSION: The nanopore technology overcomes the limitations of standard short-read sequencing techniques in SV characterization. Using nanopore, we characterized novel defects in ITGB3, HPS5, and HPS3, highlighting the utility of long-read sequencing as an additional diagnostic tool in IPDs.

2023 updated MASCC/ESMO consensus recommendations: controlling nausea and vomiting with chemotherapy of low or minimal emetic potential.

PURPOSE: Review the literature to update the MASCC guidelines from 2016 for controlling nausea and vomiting with systemic cancer treatment of low and minimal emetic potential. METHODS: A working group performed a systematic literature review using Medline, Embase, and Scopus databases between June 2015 and January 2023 of the management of antiemetic prophylaxis for anticancer therapy of low or minimal emetic potential. A consensus committee reviewed recommendations and required a consensus of 67% or greater and a change in outcome of at least 10%. RESULTS: Of 293 papers identified, 15 had information about managing systemic cancer treatment regimens of low or minimal emetic potential and/or compliance with previous management recommendations. No new evidence was reported that would change the current MASCC recommendations. No antiemetic prophylaxis is recommended for minimal emetic potential therapy, and single agents recommended for low emetic potential chemotherapy for acute emesis, but no prophylaxis is recommended for delayed emesis. Commonly, rescue medication includes antiemetics prescribed for the next higher level of emesis. CONCLUSION: There is insufficient data to change the current guidelines. Future studies should seek to more accurately determine the risk of emesis with LEC beyond the emetogenicity of the chemotherapy to include patient-related risk assessment.

SbSeI and SbSeBr micro-columnar solar cells by a novel high pressure-based synthesis process.

Van der Waals chalcogenides and chalcohalides have the potential to become the next thin film PV breakthrough, owing to the earth-abundancy and non-toxicity of their components, and their stability, high absorption coefficient and quasi-1D structure, which leads to enhanced electrical anisotropic properties when the material is oriented in a specific crystalline direction. However, quasi-1D semiconductors beyond Sb2(S,Se)3, such as SbSeX chalcohalides, have been scarcely investigated for energy generation applications, and rarely synthesised by physical vapor deposition methodologies, despite holding the promise of widening the bandgap range (opening the door to tandem or semi-transparent devices), and showing enticing new properties such as ferroelectric behaviour and defect-tolerant nature. In this work, SbSeI and SbSeBr micro-columnar solar cells have been obtained for the first time by an innovative methodology based on the selective halogenation of Sb2Se3 thin films at pressure above 1 atm. It is shown that by increasing the annealing temperature and pressure, the height and density of the micro-columnar structures grows monotonically, resulting in SbSeI single-crystal columns up to 30 µm, and tuneable morphology. In addition, solar cell prototypes with substrate configuration have shown remarkable Voc values above 550 mV and 1.8 eV bandgap.

Description of a Swine Infant Model of Volume-Controlled Hemorrhagic Shock.

Hemorrhagic shock is a leading cause of morbidity and mortality in pediatric patients. Interpretation of the clinical indicators validated in adults to guide resuscitation and comparison between different therapies is difficult in children due to the inherent heterogeneity of this population. As a result, compared to adults, appropriate management of pediatric hemorrhagic shock is still not well established. In addition, the scarcity of pediatric patients with hemorrhagic shock precludes the development of clinically relevant studies. For this reason, an experimental pediatric animal model is necessary to study the effects of hemorrhage in children as well as their response to different therapies. We present an infant animal model of volume-controlled hemorrhagic shock in anesthetized young pigs. Hemorrhage is induced by withdrawing a previously calculated blood volume, and the pig is subsequently monitored and resuscitated with different therapies. Here, we describe a precise and highly reproducible model of hemorrhagic shock in immature swine. The model yields hemodynamic data that characterizes compensatory mechanisms that are activated in response to severe hemorrhage.

Increase in Incidence Rates and Risk Factors for Multidrug Resistant Bacteria in Septic Children: A Nationwide Spanish Cohort Study (2013-2019).

The emergence of multidrug-resistant (MDR) bacteria in children is a growing concern, particularly among septic patients, given the need for first-right dosing. Our aim was to determine the incidence rates and factors associated with MDR-sepsis in the pediatric intensive care unit (PICU), using data from the Spanish ENVIN-HELICS PICU registry between 2013 and 2019. The rate of MDR bacteria among septic children ranged between 5.8 and 16.2% throughout this study period, with a significant increase since 2015 (p = 0.013). MDR-gram-negative bacteria (92%), particularly EBL-Enterobacterales (63.7%), were the most frequent causative microorganisms of MDR-sepsis. During this study period, sixteen MDR-sepsis (32.6%) corresponded to intrahospital infections, and 33 (67.4%) had community-onset sepsis, accounting for 10.5% of the overall community-onset sepsis. Independent risk factors associated with MDR-sepsis were antibiotics 48 h prior to PICU admission (OR 2.38) and PICU onset of sepsis (OR 2.58) in >1 year-old children, and previous malnourishment (OR 4.99) in <1 year-old children. Conclusions: There was an alarming increase in MDR among septic children in Spain, mainly by gram-negative (ESBL-Enterobacterales), mostly coming from the community setting. Malnourished infants and children on antibiotics 48 h prior to PICU are at increased risk and therefore require closer surveillance.

Factor XI in Carriers of Antiphospholipid Antibodies: Elevated Levels Associated with Symptomatic Thrombotic Cases, While Low Levels Linked to Asymptomatic Cases.

Antiphospholipid syndrome (APS) is a thromboinflammatory disorder caused by circulating antiphospholipid autoantibodies (aPL) and characterized by an increased risk of thrombotic events. The pathogenic mechanisms of these antibodies are complex and not fully understood, but disturbances in coagulation and fibrinolysis have been proposed to contribute to the thrombophilic state. This study aims to evaluate the role of an emerging hemostatic molecule, FXI, in the thrombotic risk of patients with aPL. Cross-sectional and observational study of 194 consecutive and unrelated cases with aPL recruited in a single center: 82 asymptomatic (AaPL) and 112 with primary antiphospholipid syndrome (APS). Clinical and epidemiological variables were collected. The profile of aPL was determined. Plasma FXI was evaluated by Western blotting and two coagulation assays (FXI:C). In cases with low FXI, molecular analysis of the F11 gene was performed. FXI:C levels were significantly higher in patients with APS than in patients with AaPL (122.8 ± 33.4 vs. 104.5 ± 27.5; p < 0.001). Multivariate analysis showed a significant association between symptomatic patients with aPL (APS) and high FXI (>150%) (OR = 11.57; 95% CI: 1.47-90.96; p = 0.020). In contrast, low FXI (<70%), mostly caused by inhibitors, was less frequent in the group of patients with APS compared to AaPL (OR = 0.17; 95%CI: 0.36-0.86; p = 0.032). This study suggests that FXI levels may play a causal role in the prothrombotic state induced by aPLs and holds the promise of complementary treatments in APS patients by targeting FXI.