Cardiovascular Risk Scales Association with Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cardiovascular Low Cardiovascular Risk Regions.

BACKGROUND: Cardiovascular risk factors are associated with Alzheimer's Disease (AD) development. However, few studies compare the overall cardiovascular risk with AD biomarkers, and when done, they are mainly performed in moderate cardiovascular risk regions. OBJECTIVES: To determine whether cardiovascular risk in older adults is associated with pathological cerebrospinal fluid (CSF) biomarkers of AD in a low cardiovascular risk population. DESIGN: This is a cross-sectional study performed between 2017 and 2020. PARTICIPANTS: The present work included patients between 50 and 75 years old who were negative for CSF AD biomarkers and had minimum cognitive alterations (controls) and patients with positive CSF AD biomarkers and in early stages of AD (cases). MEASUREMENTS: CSF biomarkers included total tau, phosphorylated tau 181 and amyloid ß42 (Aß42). Analytical variables were obtained. ERICE, SCORE2 and Framingham scales were used to calculate the overall patient's cardiovascular risk. The Aß42/Aß40 ratio and neurofilaments were explored when available. RESULTS: Two hundred and thirty-three patients were included. Nearly 76% of the sample had AD. AD patients had higher cardiovascular risk than controls (p-value < 0.05). ERICE and SCORE2 were associated with AD presence. Framingham was not. A correlation between elevated cardiovascular risk and higher total tau and NfL levels was observed when adjusted by age. CONCLUSION: Cardiovascular risk assessment may be helpful in neurodegenerative disorders detection, as it is associated with CSF total tau and NfL. ERICE and SCORE2 may be useful scales in low cardiovascular risk regions to improve cardiovascular control and prevent neurodegenerative pathologies.

State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone.

Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure-function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.

Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson's disease patients.

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[18F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (Ki), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA Ki (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA Ki loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.

Is unicentric familial papillary thyroid microcarcinoma different from multicentric?

BACKGROUND: Familial papillary thyroid microcarcinoma (FPTMC) appears to be more aggressive than sporadic papillary thyroid microcarcinoma (SPTMC). However, there are authors who indicate that unicentric FPTMC has a similar prognosis to SPTMC. The objective is to analyze whether unicentric FPTMC has a better prognosis than multicentric FPTMC. DESIGN AND METHODS: Type of study: National multicenter longitudinal analytical observational study. STUDY POPULATION: Patients with FPTMC. STUDY GROUPS: Two groups were compared: Group A (unicentric FPTMC) vs. Group B (multicentric FPTMC). STUDY VARIABLES: It is analyzed whether between the groups there are: a) differentiating characteristics; and b) prognostic differences. STATISTICAL ANALYSIS: Cox regression analysis and survival analysis. RESULTS: Ninety-four patients were included, 44% (n = 41) with unicentric FPTMC and 56% (n = 53) with multicentric FPTMC. No differences were observed between the groups according to socio-familial, clinical or histological variables. In the group B a more aggressive treatment was performed, with higher frequency of total thyroidectomy (99 vs. 78%; p = 0.003), lymph node dissection (41 vs. 15%; p = 0.005) and therapy with radioactive iodine (96 vs. 73%; p = 0.002). Tumor stage was similar in both groups (p = 0.237), with a higher number of T3 cases in the group B (24 vs. 5%; p = 0.009). After a mean follow-up of 90 ± 68.95 months, the oncological results were similar, with a similar disease persistence rate (9 vs. 5%; p = 0.337), disease recurrence rate (21 vs. 8%; p = 0.159) and disease-free survival (p = 0.075). CONCLUSIONS: Unicentric FPTMC should not be considered as a SPTMC due to its prognosis is similar to multicentric FPTMC.

A Subset of PD-1-Expressing CD56bright NK Cells Identifies Patients with Good Response to Immune Checkpoint Inhibitors in Lung Cancer.

(1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3-CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3-CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3-CD16-PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size.

Management of Patients with Suspected or Confirmed Antibiotic Allergy: Executive Summary of Guidelines from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Allergy and Clinical Immunology (SEAIC), the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Intensive Medicine and Coronary Care Units (SEMICYUC).

Suspected or confirmed antibiotic allergy is a frequent clinical circumstance that influences antimicrobial prescription and often leads to the avoidable use of less efficacious and/or more toxic or costly drugs than first-line antimicrobials. Optimizing antimicrobial therapy in patients with antibiotic allergy labels has become one of the priorities of antimicrobial stewardship programs in several countries. These guidelines aim to make recommendations for the systematic approach to patients with suspected or confirmed antibiotic allergy based on current evidence. An expert panel (11 members of various scientific societies) formulated questions about the management of patients with suspected or confirmed antibiotic allergy. A systematic literature review was performed by a medical librarian. The questions were distributed among panel members who selected the most relevant references, summarized the evidence, and formulated graded recommendations when possible. The answers to all the questions were finally reviewed by all panel members. A systematic approach to patients with suspected or confirmed antibiotic allergy was recommended to improve antibiotic selection and, consequently, clinical outcomes. A clinically oriented, 3-category risk-stratification strategy was recommended for patients with suspected antibiotic allergy. Complementary assessments should consider both clinical risk category and preferred antibiotic agent. Empirical therapy recommendations for the most relevant clinical syndromes in patients with suspected or confirmed ß-lactam allergy were formulated, as were recommendations on the implementation and monitoring of the impact of the guidelines. Antimicrobial stewardship programs and allergists should design and implement activities that facilitate the most appropriate use of antibiotics in these patients.

Management of Patients with Suspected or Confirmed Antibiotic Allergy: Executive Summary of Guidelines from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Allergy and Clinical Immunology (SEAIC), the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Intensive Medicine and Coronary Care Units (SEMICYUC)

Suspected or confirmed antibiotic allergy is a frequent clinical circumstance that influences antimicrobial prescription and often leads to the avoidable use of less efficacious and/or more toxic or costly drugs than first-line antimicrobials. Optimizing antimicrobial therapy in patients with antibiotic allergy labels has become one of the priorities of antimicrobial stewardship programs in several countries. These guidelines aim to make recommendations for the systematic approach to patients with suspected or confirmed antibiotic allergy based on current evidence. An expert panel (11 members of various scientific societies) formulated questions about the management of patients with suspected or confirmed antibiotic allergy. A systematic literature review was performed by a medical librarian. The questions were distributed among panel members who selected the most relevant references, summarized the evidence, and formulated graded recommendations when possible. The answers to all the questions were finally reviewed by all panel members. A systematic approach to patients with suspected or confirmed antibiotic allergy was recommended to improve antibiotic selection and, consequently, clinical outcomes. A clinically oriented, 3-category risk-stratification strategy was recommended for patients with suspected antibiotic allergy. Complementary assessments should consider both clinical risk category and preferred antibiotic agent. Empirical therapy recommendations for the most relevant clinical syndromes in patients with suspected or confirmed ß-lactam allergy were formulated, as were recommendations on the implementation and monitoring of the impact of the guidelines. Antimicrobial stewardship programs and allergists should design and implement activities that facilitate the most appropriate use of antibiotics in these patients (AU)

En la práctica clínica, un antecedente de alergia a los antibióticos, confirmada o sospechada, es frecuente y condiciona la selección de antibióticos, requiriendo con frecuencia el uso de fármacos menos eficaces, más tóxicos o más caros que los antibióticos de primera línea. La optimización del uso de antibióticos en pacientes con este antecedente es una de las prioridades de los programas de optimización de uso de antibióticos (PROA) en varios países. Estas guías pretenden formular recomendaciones para evaluar de una manera sistemática a estos pacientes mediante una aproximación basada en la evidencia. Un panel multidisciplinar constituido por alergólogos, infectólogos, farmacéuticos hospitalarios e intensivistas formularon una serie de preguntas sobre el manejo de estos pacientes; una documentalista realizó la revisión bibliográfica. Las preguntas se distribuyeron entre los miembros del grupo de trabajo, quienes seleccionaron las referencias más relevantes y formularon las correspondientes recomendaciones, que fueron revisadas y aprobadas por todos los miembros del grupo. Es necesaria una aproximación sistemática a los pacientes con antecedentes de alergia a antibióticos para optimizar la selección del tratamiento antibiótico y mejorar los resultados clínicos de estos pacientes cuando precisan antibioterapia. El presente documento recomienda una estrategia de estratificación clínica del riesgo en 3 categorías. La recomendación de realizar evaluaciones complementarias se basa en el riesgo clínico y el antibiótico de primera línea necesario. Además, se formulan recomendaciones de tratamiento antibiótico empírico para los principales síndromes infecciosos en pacientes con alergia confirmada o sospechada. Finalmente, se formulan recomendaciones sobre la implementación y monitorización del impacto de las recomendaciones de la guía (AU)

KLF17 is an important regulatory component of the transcriptomic response of Atlantic salmon macrophages to Piscirickettsia salmonis infection.

Piscirickettsia salmonis is the most important health problem facing Chilean Aquaculture. Previous reports suggest that P. salmonis can survive in salmonid macrophages by interfering with the host immune response. However, the relevant aspects of the molecular pathogenesis of P. salmonis have been poorly characterized. In this work, we evaluated the transcriptomic changes in macrophage-like cell line SHK-1 infected with P. salmonis at 24- and 48-hours post-infection (hpi) and generated network models of the macrophage response to the infection using co-expression analysis and regulatory transcription factor-target gene information. Transcriptomic analysis showed that 635 genes were differentially expressed after 24- and/or 48-hpi. The pattern of expression of these genes was analyzed by weighted co-expression network analysis (WGCNA), which classified genes into 4 modules of expression, comprising early responses to the bacterium. Induced genes included genes involved in metabolism and cell differentiation, intracellular transportation, and cytoskeleton reorganization, while repressed genes included genes involved in extracellular matrix organization and RNA metabolism. To understand how these expression changes are orchestrated and to pinpoint relevant transcription factors (TFs) controlling the response, we established a curated database of TF-target gene regulatory interactions in Salmo salar, SalSaDB. Using this resource, together with co-expression module data, we generated infection context-specific networks that were analyzed to determine highly connected TF nodes. We found that the most connected TF of the 24- and 48-hpi response networks is KLF17, an ortholog of the KLF4 TF involved in the polarization of macrophages to an M2-phenotype in mammals. Interestingly, while KLF17 is induced by P. salmonis infection, other TFs, such as NOTCH3 and NFATC1, whose orthologs in mammals are related to M1-like macrophages, are repressed. In sum, our results suggest the induction of early regulatory events associated with an M2-like phenotype of macrophages that drives effectors related to the lysosome, RNA metabolism, cytoskeleton organization, and extracellular matrix remodeling. Moreover, the M1-like response seems delayed in generating an effective response, suggesting a polarization towards M2-like macrophages that allows the survival of P. salmonis. This work also contributes to SalSaDB, a curated database of TF-target gene interactions that is freely available for the Atlantic salmon community.

Biological behavior of familial papillary thyroid microcarcinoma: Spanish multicenter study.

PURPOSE: Familial papillary thyroid microcarcinoma (FPTMC) can present a more aggressive behavior than the sporadic microcarcinoma. However, few studies have analyzed this situation. The objective is to analyze the recurrence rate of FPTMC and the prognostic factors which determine that recurrence in Spain. METHODS: Spanish multicenter longitudinal analytical observational study was conducted. Patients with FPTMC received treatment with curative intent and presented cure criteria 6 months after treatment. Recurrence rate and disease-free survival (DFS) were analyzed. Two groups were analyzed: group A (no tumor recurrence) vs. group B (tumor recurrence). RESULTS: Ninety-four patients were analyzed. During a mean follow-up of 73.3 ± 59.3 months, 13 recurrences of FPTMC (13.83%) were detected and mean DFS was 207.9 ± 11.5 months. There were multifocality in 56%, bilateral thyroid involvement in 30%, and vascular invasion in 7.5%; that is to say, they are tumors with histological factors of poor prognosis in a high percentage of cases. The main risk factors for recurrence obtained in the multivariate analysis were the tumor size (OR: 2.574, 95% CI 1.210-5.473; p = 0.014) and the assessment of the risk of recurrence of the American Thyroid Association (ATA), both intermediate risk versus low risk (OR: 125, 95% CI 10.638-1000; p < 0.001) and high risk versus low risk (OR: 45.454, 95% CI 5.405-333.333; p < 0.001). CONCLUSION: FPTMC has a recurrence rate higher than sporadic cases. Poor prognosis is mainly associated with the tumor size and the risk of recurrence of the ATA.

A finely tuned interplay between calcium binding, ionic strength and pH modulates conformational and oligomerization equilibria in the Respiratory Syncytial Virus Matrix (M) protein.

As in most enveloped RNA viruses, the Respiratory Syncytial Virus Matrix (RSV-M) protein plays key roles in viral assembly and uncoating. It also plays non-structural roles related to transcription modulation through nucleo-cytoplasmic shuttling and nucleic acid binding ability. We dissected the structural and conformational changes underlying the switch between multiple functionalities, identifying Ca2+ binding as a key factor. To this end, we tackled the analysis of M's conformational stability and equilibria. While in silico calculations predict two potential calcium binding sites per protomer, purified RSV-M dimer contains only one strongly bound calcium ion per protomer. Incubation of RSV-M in the presence of excess Ca2+ leads to an increase in the thermal stability, confirming additional Ca2+ binding sites. Moreover, mild denaturant concentrations trigger the formation of higher order oligomers which are otherwise prevented under Ca2+ saturation conditions, in line with the stabilizing effect of the additional low affinity binding site. On the other hand, Ca2+ removal by chelation at pH 7.0 causes a substantial decrease in the thermal stability leading to the formation of amorphous, spherical-like aggregates, as assessed by TEM. Even though the Ca2+ content modulates RSV-M oligomerization propensity, it does affect its weak RNA binding ability. RSV-M undergoes a substantial conformational change at pHs 4.0 to 5.0 that results in the exposure of hydrophobic surfaces, an increase beta sheet content but burial of tryptophan residues. While low ionic strength promotes dimer dissociation at pH 4.0, physiological concentrations of NaCl lead to the formation of soluble oligomers smaller than 400 kDa at pH 4.0 or insoluble aggregates with tubular morphology at pH 5.0, supporting a fine tuning by pH. Furthermore, the dissociation constants estimated for the low- and high affinity calcium binding sites are 13 µM and 58 nM, respectively, suggesting an intracellular calcium sensing mechanism of RSV-M upon infection. We uncover a finely tuned interplay between calcium binding, ionic strength, and pH changes compatible with the different cellular compartments where M plays key roles, revealing diverse conformational equilibria, oligomerization, and high order structures, required to stabilize the virion particle by a layer of molecules positioned between the membrane and the nucleocapsid.

Traditional sexing methods and external egg characteristics combination allow highly accurate early sex determination in an endangered native turkey breed.

Early sex determination methods are not only crucial in the worldwide massive poultry industry, but also for small-holder producers. The profitability of sexing techniques must be accounted for when aiming to boost management, nutrition, and conservation practices in endangered poultry breeds. This becomes pivotal when the local breed dealt with belongs to an understudied species, such as the turkey. So, the main objective of this study is to identify which method combination may report a higher likelihood of successful sex determination in poults across the three-pattern varieties of the Andalusian turkey breed. A total of 84 one to two days old Andalusian turkey poults (42 black, 28 black-roan, and 14 bronze-roan) were evaluated in this study. Sex determination was performed using 15 methods, which included testing external egg metrics and eggshell color, poult morphological appraisal and phaneroptics, and behavioral traits. Possible differences across plumage varieties and the interaction between sex and plumage were observed when external egg quality was measured. Sex determination through behavioral methods in black base feathered (black and black-roan) male sex individuals showed seven times higher sensitivity when compared to the rest of the studied individuals (χ2 = 7.14, df = 1, P < 0.01). In contrast, for the black-roan plumage females, the method based on the color of down feathers was approximately four times more sensitive (χ2 = 3.95, df = 1, P ≤ 0.05). For the bronze-roan pattern, none of the sexing techniques was reported to efficiently predict sex itself. However, the most proper method combination to determine sex, independent of plumage color, was physical external egg characteristics, the color of down feathers, and behavioral approaches ("English method" and "slap technique"). The specificity values were found to be 49.12, 93.33, and 100%, while the sensitivity values were observed to be 74.64, 91.03, and 100%, which translated into accuracy of 63.10, 92.26, and 100% in black, black-roan, and bronze-roan poults, respectively. Our results suggest that the method combination tested in this study could be considered a highly accurate, simple, and affordable alternative for sex determination in turkeys. This could mean a pivotal advance for small producers of turkeys, as early sex detection can help to plan timely conservational management strategies, which is of prominent importance in the context of endangered poultry breeds.

Estado de situación como potencial herramienta para analizar factores de riesgo de deterioro cognitivo. Estudio piloto desde una farmacia rural / State of play as a potential tool to analyse risk factors for cognitive impairment. Pilot study from a rural pharmacy

JUSTIFICACIÓN: la esperanza de vida en España aumenta de forma ininterrumpida. El envejecimiento implica mayor prevalencia de patologías crónicas, polifarmacia, Problemas Relacionados con Medicamentos (PRM) y Resultados Negativos Asociados a la Medicación (RNM), lo cual puede conllevar una mayor probabilidad de desarrollar deterioro cognitivo (DC). Por ello, es importante detectar aquellos factores implicados que puedan aumentar el riesgo de DC.OBJETIVOS: analizar, a través de un estado de situación, información relevante sobre factores de riesgo de deterioro cognitivo y detectar posibles PRM/RNM.MATERIAL Y MÉTODOS: estudio observacional- transversal en personas mayores de 50 años que viven en una población inferior a 400 habitantes. Mediante entrevista personal en la zona de atención personalizada de la farmacia, se llevó a cabo una revisión del uso de la medicación (RUM) según protocolo REVISA®. Siguiendo el método DADER, se realizó un estado de situación individualizado registrando problemas de salud (CIE-10), tratamientos farmacológicos y posologías (ATC/DDD), datos analíticos y otros datos de interés. Se utilizó la plataforma BotPlus para analizar interacciones farmacológicas y detectar posibles PRM y RNM. Se calculó el riesgo cardiovascular (RCV) individual mediante la ecuación ERICE. Se clasificaron los pacientes en dos grupos en función de si presentaban puntuaciones compatibles con DC o no a los test MIS, Pfeiffer y Fluidez verbal. Se realizaron cálculos estadísticos mediante el test no paramétrico de Wilcoxon y chi-cuadrado para comparar las variables entre los dos grupos. Dicho estudio fue aprobado por el comité de ética (CEI21/222). Todos los pacientes firmaron el consentimiento informado.RESULTADOS/DISCUSIÓN: se analizaron 47 estados de situación, de los cuales 16 pacientes (34 %) presentaron puntuaciones compatibles con DC. (AU)

SEA 2022 Standards for Global Control of Cardiovascular Risk. / Estándares SEA 2022 para el control global del riesgo cardiovascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to better knowledge of vascular disease, its prevention and treatment. It is well known that cardiovascular diseases are the leading cause of death in our country and entail a high degree of disability and health care costs. Arteriosclerosis is a multifactorial disease and therefore its prevention requires a global approach that takes into account the different risk factors with which it is associated. Therefore, this document summarizes the current level of knowledge and includes recommendations and procedures to be followed in patients with established cardiovascular disease or at high vascular risk. Specifically, this document reviews the main symptoms and signs to be evaluated during the clinical visit, the laboratory and imaging procedures to be routinely requested or requested for those in special situations. It also includes vascular risk estimation, the diagnostic criteria of the different entities that are cardiovascular risk factors, and makes general and specific recommendations for the treatment of the different cardiovascular risk factors and their final objectives. Finally, the document includes aspects that are not usually referenced in the literature, such as the organization of a vascular risk consultation.

Changes in severity, mortality, and virus genome among a Spanish cohort of patients hospitalized with SARS-CoV-2.

Comparing pandemic waves could aid in understanding the evolution of COVID-19. The objective of the present study was to compare the characteristics and outcomes of patients hospitalized for COVID-19 in different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of 5,220 patients hospitalized with SARS-CoV-2 infection from February to September 2020 in Aragon, Spain. We compared ICU admissions and 30-day mortality, clinical characteristics, and risk factors of the first and second waves of COVID-19. The SARS-CoV-2 genome was also analyzed in 236 samples. Patients in the first wave (n = 2,547) were older (median age 74 years [IQR 60-86] vs. 70 years [53-85]; p < 0.001) and had worse clinical and analytical parameters related to severe COVID-19 than patients in the second wave (n = 2,673). The probability of ICU admission at 30 days was 16% and 10% (p < 0.001) and the cumulative 30-day mortality rates 38% and 32% in the first and second wave, respectively (p = 0.007). Survival differences were observed among patients aged 60 to 80 years. We also found some variability among death risk factors and the viral genome between waves. Therefore, the two analyzed COVID-19 pandemic waves were different in terms of disease severity and mortality.

Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes

Background and purpose Synchronous bilateral breast cancer (SBBC) accounts for 1–3.5% of breast cancer patients. The aim of this study was to evaluate dosimetric issues, clinical outcomes, and acute toxicities for SBBC patients receiving synchronous bilateral hypofractionated radiotherapy (SBHRT) and to compare them with patients treated with synchronous bilateral normofractionated RT schedule (SBNRT). Materials and methods From April 2016 to March 2020, 39 SBBC patients were referred to our institution. Patients were divided according to their prescription dose: Group A: 50 Gy/25fx (fractions), B: 60–64 Gy/25fx, C: 40.05 Gy/15fx; D: 48 Gy/15fx. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE)v.5.0. Results 34 patients were finally evaluated. Median follow-up was 24 months for NF schedule and 9 months for HF schedule. In the HF schedule, no acute side-effects > G2 were observed and no dermatitis was reported in 6th month´s assessments. 95% of patients have no evidence of disease and only 1 patient presented local relapse in the first mammography after RT. No distant failures or deaths were observed. Regarding dosimetric issues, the inter-patient average Dmean for the heart was: Group A: 5.0 Gy (4.6–5.5), Group B: 4.4 Gy (4.1–5.4), Group C: 4.8 Gy (4.5–5.1) and Group D: 5.3 Gy (4.4–5.6). For the lungs, the inter-patient average Dmean was: Group A: 10.8 Gy (9.8–12.2), Group B: 11.5 Gy (11.3–12), Group C: 9.8 Gy (9.3–10.5) and Group D: 10.5 Gy (10–11.3). Conclusions This is the first study reporting the safety, feasibility, and tolerability of 40.05 Gy/15fx over 3 weeks for the treatment of SBBC patients. Further study with larger accrual is mandatory (AU)

The sulphur saga in TMC-1: Discovery of HCSCN and HCSCCH.

We report the detection, for the first time in space, of cyano thioformaldehyde (HCSCN) and propynethial (HCSCCH) towards the starless core TMC-1. Cyano thioformaldehyde presents a series of prominent a- and b-type lines, which are the strongest previously unassigned features in our Q-band line survey of TMC-1. Remarkably, HCSCN is four times more abundant than cyano formaldehyde (HCOCN). On the other hand, HCSCCH is five times less abundant than propynal (HCOCCH). Surprisingly, we find an abundance ratio HCSCCH/HCSCN of ∼ 0.25, in contrast with most other ethynyl-cyanide pairs of molecules for which the CCH-bearing species is more abundant than the CN-bearing one. We discuss the formation of these molecules in terms of neutral-neutral reactions of S atoms with CH2CCH and CH2CN radicals as well as of CCH and CN radicals with H2CS. The calculated abundances for the sulphur-bearing species are, however, significantly below the observed values, which points to an underestimation of the abundance of atomic sulphur in the model or to missing formation reactions, such as ion-neutral reactions.

Cumulene carbenes in TMC-1: Astronomical discovery of l-H2C5 ☠.

We report the first detection in space of the cumulene carbon chain l-H2C5. A total of eleven rotational transitions, with Jup = 7-10 and Ka = 0 and 1, were detected in TMC-1 in the 31.0-50.4 GHz range using the Yebes 40m radio telescope. We derive a column density of (1.8±0.5)×1010 cm-2. In addition, we report observations of other cumulene carbenes detected previously in TMC-1, to compare their abundances with the newly detected cumulene carbene chain. We find that l-H2C5 is ~4.0 times less abundant than the larger cumulene carbene l-H2C6, while it is ~300 and ~500 times less abundant than the shorter chains l-H2C3 and l-H2C4. We discuss the most likely gas-phase chemical routes to these cumulenes in TMC-1 and stress that chemical kinetics studies able to distinguish between different isomers are needed to shed light on the chemistry of C n H2 isomers with n > 3.

A Clinical Decision Web to Predict ICU Admission or Death for Patients Hospitalised with COVID-19 Using Machine Learning Algorithms.

The purpose of the study was to build a predictive model for estimating the risk of ICU admission or mortality among patients hospitalized with COVID-19 and provide a user-friendly tool to assist clinicians in the decision-making process. The study cohort comprised 3623 patients with confirmed COVID-19 who were hospitalized in the SALUD hospital network of Aragon (Spain), which includes 23 hospitals, between February 2020 and January 2021, a period that includes several pandemic waves. Up to 165 variables were analysed, including demographics, comorbidity, chronic drugs, vital signs, and laboratory data. To build the predictive models, different techniques and machine learning (ML) algorithms were explored: multilayer perceptron, random forest, and extreme gradient boosting (XGBoost). A reduction dimensionality procedure was used to minimize the features to 20, ensuring feasible use of the tool in practice. Our model was validated both internally and externally. We also assessed its calibration and provide an analysis of the optimal cut-off points depending on the metric to be optimized. The best performing algorithm was XGBoost. The final model achieved good discrimination for the external validation set (AUC = 0.821, 95% CI 0.787-0.854) and accurate calibration (slope = 1, intercept = -0.12). A cut-off of 0.4 provides a sensitivity and specificity of 0.71 and 0.78, respectively. In conclusion, we built a risk prediction model from a large amount of data from several pandemic waves, which had good calibration and discrimination ability. We also created a user-friendly web application that can aid rapid decision-making in clinical practice.

Pure hydrocarbon cycles in TMC-1: Discovery of ethynyl cyclopropenylidene, cyclopentadiene and indene.

We report the detection for the first time in space of three new pure hydrocarbon cycles in TMC-1: c-C3HCCH (ethynyl cyclopropenylidene), c-C5H6 (cyclopentadiene) and c-C9H8 (indene). We derive a column density of 3.1 × 1011 cm-2 for the former cycle and similar values, in the range (1-2) × 1013 cm-2, for the two latter molecules. This means that cyclopentadiene and indene, in spite of their large size, are exceptionally abundant, only a factor of five less abundant than the ubiquitous cyclic hydrocarbon c-C3H2. The high abundance found for these two hydrocarbon cycles, together with the high abundance previously found for the propargyl radical (CH2CCH) and other hydrocarbons like vinyl and allenyl acetylene (Agúndez et al. 2021; Cernicharo et al. 2021a,b), start to allow us to quantify the abundant content of hydrocarbon rings in cold dark clouds and to identify the intermediate species that are probably behind the in situ bottom-up synthesis of aromatic cycles in these environments. While c-C3HCCH is most likely formed through the reaction between the radical CCH and c-C3H2, the high observed abundances of cyclopentadiene and indene are difficult to explain through currently proposed chemical mechanisms. Further studies are needed to identify how are five- and six-membered rings formed under the cold conditions of clouds like TMC-1.

Statistical control of processes applied to geometric uncertainties for CTV expansion margins determination in prostate cancer patients treated with VMAT: a prospective study in 57 patients

Purpose To study the control graphs applicability for the geometric uncertainties of VMAT treatments in prostate cancer patients, and their use to verify the hypothesis of the data obtained randomness, to apply the margins of Van Herk expression. Material and methods During the first 5 days of treatment, and then once a week, a Kv CBCT was performed, compared with the simulation CT and adjusted the displacements, to determine the inter-fraction errors. Immediately after radiation therapy, another CBCT was performed (for intra-fraction errors). With these data, the X, R position control charts have been made. The patients, not maintained the deviations within the charts control limits, were called “anomalies”. Then, we compared the deviations and margins calculated with the van Herk expression for all patients and for those without anomalies. Results The margins determined show appreciable differences if there were calculated for the total set of patients or for the set of them without anomalies in the control charts. For the overall set of patients, the lateral, longitudinal, and vertical margins were 0.45 cm, 0.52 cm, 0.56 cm, while for the set of patients without anomalies were 0.29 cm, 0.35 cm, and 0.38 cm. Conclusions The use of control charts allows tracking geometric deviations both inter and intra-fraction, variability real-time control and to detect situations in which it can change for non-random reasons, and require immediate investigation. Maintaining geometric deviations in the control state decreases the margins needed to administer a high dose to CTV in a high percentage of cancer prostate patients (AU)