Collaborating with cancer patients and informal caregivers in a European study on quality of life: protocol to embed patient and public involvement within the EUonQoL project.

BACKGROUND: Patient and public involvement (PPI) has become an essential part of health research. There is a need for genuine involvement in order to ensure that research is relevant to patients. This can then improve the quality, relevance, and impact of health research, while at the same time reducing wasted research and in doing so bringing science and society closer together. Despite the increasing attention for this involvement, it is not yet common practice to report on proposed activities. An article reporting planned PPI could provide guidance and inspiration for the wider academic community in future activities. Therefore, this current article aims to describe the way in which PPI principles are incorporated in the research project called "Quality of Life in Oncology: measuring what matters for cancer patients and survivors in Europe (EUonQoL)." This project aims to develop a new set of questionnaires to enable cancer patients to assess their quality of life, entitled the EUonQoL-Kit. METHODS: The first step is to recruit cancer patients and their informal caregivers as co-researchers in order to train them to collaborate with the researchers. Based on their skills and preferences, they are then assigned to several of the project's work packages. Their individual roles, tasks, and responsibilities regarding the work packages, to which they have been assigned, are evaluated and adapted when necessary. The impact of their involvement is evaluated by both the researchers and co-researchers. DISCUSSION: PPI is a complex and dynamic process. As such, the overall structure of the research may be defined while at the same time leaving room for certain aspects to be filled in later. Our research is, we believe, relevant as co-researcher involvement in such a large European project as EUonQoL is a new development.

Analysis of machine learning algorithmic models for the prediction of vital status at six months after hip fracture in patients older than 74 years. / Análisis de modelos algorítmicos de aprendizaje automático para la predicción del estado vital a los seis meses tras fractura de cadera en pacientes mayores de 74 años.

BACKGROUND AND OBJECTIVE: The objective is to develop a model that predicts vital status six months after fracture as accurately as possible. For this purpose we will use five different data sources obtained through the National Hip Fracture Registry, the Health Management Unit and the Economic Management Department. MATERIAL AND METHODS: The study population is a cohort of patients over 74 years of age who suffered a hip fracture between May 2020 and December 2022. A warehouse is created from five different data sources with the necessary variables. An analysis of missing values and outliers as well as unbalanced classes of the target variable («vital status¼) is performed. Fourteen different algorithmic models are trained with the training. The model with the best performance is selected and a fine tuning is performed. Finally, the performance of the selected model is analyzed with test data. RESULTS: A data warehouse is created with 502 patients and 144 variables. The best performing model is Linear Regression. Sixteen of the 24 cases of deceased patients are classified as live, and 14 live patients are classified as deceased. A sensitivity of 31%, an accuracy of 34% and an area under the curve of 0.65 is achieved. CONCLUSIONS: We have not been able to generate a model for the prediction of six-month survival in the current cohort. However, we believe that the method used for the generation of algorithms based on machine learning can serve as a reference for future works.

Structural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements.

RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with the chaperone HSP90 and the cochaperone CDC37. Understanding the intricate molecular interactions governing RAF1 folding is crucial for comprehending this process. Here, we present a cryo-EM structure of the closed-state RAF1-HSP90-CDC37 complex, where the C-lobe of the RAF1 kinase domain binds to one side of the HSP90 dimer, and an unfolded N-lobe segment of the RAF1 kinase domain threads through the center of the HSP90 dimer. CDC37 binds to the kinase C-lobe, mimicking the N-lobe with its HxNI motif. We also describe structures of HSP90 dimers without RAF1 and CDC37, displaying only N-terminal and middle domains, which we term the semi-open state. Employing 1 µs atomistic simulations, energetic decomposition, and comparative structural analysis, we elucidate the dynamics and interactions within these complexes. Our quantitative analysis reveals that CDC37 bridges the HSP90-RAF1 interaction, RAF1 binds HSP90 asymmetrically, and that HSP90 structural elements engage RAF1's unfolded region. Additionally, N- and C-terminal interactions stabilize HSP90 dimers, and molecular interactions in HSP90 dimers rearrange between the closed and semi-open states. Our findings provide valuable insight into the contributions of HSP90 and CDC37 in mediating client folding.

Admisiones en los servicios de urgencias y costes económicos relacionados con procesos susceptibles de atención ambulatoria en adultos mayores que viven en centros residenciales / Emergency department admissions and economic costs burden related to ambulatory care sensitive conditions in older adults living in care homes

Objetivos Evaluar la frecuencia de las admisiones en los servicios de urgencias (ASU) por ambulatory care sensitive conditions (ACSC) y no-ACSC de personas que viven en residencias; describir y comparar sus características, y analizar los costes asociados. Método Este estudio multicéntrico, retrospectivo y observacional evaluó 2.444ASU de personas ≥65 años que viven en residencias en 5 servicios de urgencias de Cataluña por ACSC y no-ACSC, en 2017. Se recogieron variables sociodemográficas, estado funcional y cognitivo, e información sobre diagnóstico y hospitalización. Se evaluaron los costes relacionados con ACSC-ASU y se efectuó un análisis de sensibilidad utilizando diferentes supuestos de disminución de ingresos por ACSC. Resultados La media de edad de la muestra del estudio fue de 85,9 años (desviación estándar: 7,2 años). La frecuencia de ACSC-ASU y no-ACSC-ASU fue del 56,6 y el 43,4%, respectivamente. El 56,6 y el 78% presentaban dependencia severa y deterioro cognitivo, respectivamente, sin observarse diferencias entre los 2 grupos. Las 3 ACSC más frecuentes fueron caídas/traumatismos (13,8%), enfermedad pulmonar obstructiva crónica/asma (11,4%) e infección urinaria (7,4%). El coste medio por ACSC-ASU fue de 1.408,24€. Suponiendo una reducción del 60% de las ACSC-ASU, el ahorro de costes estimado sería de 1,2 millones de euros. Conclusiones Las admisiones en urgencias por ACSC procedentes de entornos residenciales suponen un impacto significativo tanto en la frecuencia como en los costes. La disminución de estas enfermedades mediante la aplicación de intervenciones específicas podría redirigir los costes evitados hacia la mejora del apoyo asistencial en los entornos residenciales (AU)

Objectives To assess the frequency of emergency department admissions (EDAs) for ambulatory care sensitive conditions (ACSC) and non-ACSC among older adults living in care homes (CH), to describe and compare their demographic and clinical characteristics, the outcomes of the hospitalization process and the associated costs. Method This multicenter, retrospective and observational study evaluated 2444 EDAs of older adults ≥65 years old living in care homes in five emergency departments in Catalonia (Spain) by ACSC and non-ACSC, in 2017. Sociodemographic variables, prior functional and cognitive status, and information on diagnosis and hospitalization were collected. Additionally, the costs related with the EDAs were calculated, as well as a sensitivity analysis using different assumptions of decreased admissions due to ACSC Results A total of 2444 ED admissions were analyzed. The patients’ mean (SD) age was 85.9 (7.2) years. The frequency of ACSC-EDA and non-ACSC-EDA was 56.6% and 43.4%, respectively. Severe dependency and cognitive impairment were present in 56.6% and 78%, respectively, with no differences between the two groups. The three most frequent ACSC were falls/trauma (13.8%), chronic obstructive pulmonary disease/asthma (11.4%) and urinary tract infection (7.4%). The average cost per ACSC-EDA was €1408.24. Assuming a 60% reduction of ACSC-EDA, the estimated cost savings would be €1.2 million. Conclusions Emergency admissions for ACSC from care homes have a significant impact on both frequency and costs. Reducing these conditions through targeted interventions could redirect the avoided costs toward improving care support in residential settings (AU)

Emergency department admissions and economic costs burden related to ambulatory care sensitive conditions in older adults living in care homes.

OBJECTIVES: To assess the frequency of emergency department admissions (EDA) for ambulatory care sensitive conditions (ACSC) and non-ACSC among older adults living in care homes (CH), to describe and compare their demographic and clinical characteristics, the outcomes of the hospitalisation process and the associated costs. METHOD: This multicenter, retrospective and observational study evaluated 2444 EDAs of older adults ≥ 65 years old living in care homes in 5 emergency departments in Catalonia (Spain) by ACSC and non-ACSC, in 2017. Sociodemographic variables, prior functional and cognitive status, and information on diagnosis and hospitalisation were collected. Additionally, the costs related with the EDAs were calculated, as well as a sensitivity analysis using different assumptions of decreased admissions due to ACSC. RESULTS: A total of 2444 ED admissions were analysed. The patients' mean (SD) age was 85.9 (7.2) years. The frequency of ACSC-EDA and non-ACSC-EDA was 56.6% and 43.4%, respectively. Severe dependency and cognitive impairment were present in 56.6% and 78%, respectively, with no differences between the two groups. The three most frequent ACSC were falls/trauma (13.8%), chronic obstructive pulmonary disease/asthma (11.4%) and urinary tract infection (7.4%). The average cost per ACSC-EDA was є1,408.24. Assuming a 60% reduction of ACSC-EDA, the estimated cost savings would be є1.2 million. CONCLUSIONS: Emergency admissions for ACSC from care homes have a significant impact on both frequency and costs. Reducing these conditions through targeted interventions could redirect the avoided costs towards improving care support in residential settings.

Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.

SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of the SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS, and PP1C form a stable ternary complex in which all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex forms only when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation and how mutations found in Noonan syndrome enhance complex formation, and reveal new avenues for therapeutic interventions.

Effectiveness of a Weight-Loss Intervention in Preventing Frailty and Functional Decline in Community-Dwelling Obese Older People. A Randomized Controlled Trial.

BACKGROUND: Obesity is a risk factor for frailty and muscle weakness, so weight loss in obese older adults may prevent frailty and functional decline. OBJECTIVE: To assess the safety and efficacy of a multimodal weight-loss intervention in improving functional performance and reducing frailty risk in obese older adults. DESIGN: Randomized controlled trial with 2 parallel arms. SETTING AND PARTICIPANTS: Community-dwelling obese adults aged 65-75 years with body mass index (BMI) 30-39 kg/m2. INTERVENTION: 6-month multimodal intervention based on diet and a physical activity program. CONTROL GROUP: Usual care. Main and secondary outcome measures: Frailty (Fried criteria) rate and functional performance at 6, 12, and 24 months of follow-up, respectively. Intermediate outcome measures: Weight loss, body composition changes, and metabolic and inflammatory biomarker changes. RESULTS: N=305. The study intervention increased gait speed at 12 and 24 months of follow-up, but had no significant effect on frailty prevention. It was effective in reducing weight, BMI, fat mass, interleukin 6, and insulin resistance and improving self-reported quality of life. CONCLUSIONS: The study intervention was not demonstrated to be effective in preventing frailty in obese people aged 65-75 years at 24 months of follow-up. However, it allowed weight loss and a reduction in inflammatory and insulin resistance markers, which could have a long-term effect on frailty that requires further research.

Use of healthcare REsources and associated COsts in controlled versus uncontrolled carcinoid SYndrome in patients with neuroendocrine tumours: the RECOSY study

Purpose To report healthcare resource use and associated costs in controlled versus uncontrolled carcinoid syndrome (CS) in patients with neuroendocrine tumours. Methods A cross-sectional, non-interventional multicentre study was conducted with retrospective data analysis. Resource use was compared between two patient groups: those with controlled CS (> 12 months with no uncontrolled CS episodes) and uncontrolled CS (< 12 months since last uncontrolled episode). Patients were matched for age, sex, and origin and grade of tumour. When no matching patients were available, data from deceased patients were used. Information on healthcare resource use came from review of medical records, patient history and physician reports. Working capacity was assessed using the Work Productivity and Activity Impairment General Health questionnaire. Results Twenty-six university hospitals in Spain participated, between July 2017 and April 2018. 137 patients were enrolled; 104 were analysed (2 groups of 52). Patients with uncontrolled CS had 10 times more emergency department (ED) visits (mean 1.0 vs 0.10 visits; P = 0.0167), were more likely to have a hospital admission (40.4% vs 19.2%; P = 0.0116) and had longer hospital stays (mean 7.87 vs 2.10 days; P = 0.0178) than those with controlled CS. This corresponded to higher annual hospitalisation costs (mean €5511.59 vs €1457.22; P = 0.028) and ED costs (€161.25 vs €14.85; P = 0.0236). The mean annual total healthcare costs were 60.0% higher in patients with uncontrolled than controlled CS (P = NS). Conclusion This study quantifies higher health resource use, and higher hospitalisation and ED costs in patients with uncontrolled CS. Better control of CS may result 3in lower medical costs (AU)

Use of healthcare REsources and associated COsts in controlled versus uncontrolled carcinoid SYndrome in patients with neuroendocrine tumours: the RECOSY study.

PURPOSE: To report healthcare resource use and associated costs in controlled versus uncontrolled carcinoid syndrome (CS) in patients with neuroendocrine tumours. METHODS: A cross-sectional, non-interventional multicentre study was conducted with retrospective data analysis. Resource use was compared between two patient groups: those with controlled CS (> 12 months with no uncontrolled CS episodes) and uncontrolled CS (< 12 months since last uncontrolled episode). Patients were matched for age, sex, and origin and grade of tumour. When no matching patients were available, data from deceased patients were used. Information on healthcare resource use came from review of medical records, patient history and physician reports. Working capacity was assessed using the Work Productivity and Activity Impairment General Health questionnaire. RESULTS: Twenty-six university hospitals in Spain participated, between July 2017 and April 2018. 137 patients were enrolled; 104 were analysed (2 groups of 52). Patients with uncontrolled CS had 10 times more emergency department (ED) visits (mean 1.0 vs 0.10 visits; P = 0.0167), were more likely to have a hospital admission (40.4% vs 19.2%; P = 0.0116) and had longer hospital stays (mean 7.87 vs 2.10 days; P = 0.0178) than those with controlled CS. This corresponded to higher annual hospitalisation costs (mean €5511.59 vs €1457.22; P = 0.028) and ED costs (€161.25 vs €14.85; P = 0.0236). The mean annual total healthcare costs were 60.0% higher in patients with uncontrolled than controlled CS (P = NS). CONCLUSION: This study quantifies higher health resource use, and higher hospitalisation and ED costs in patients with uncontrolled CS. Better control of CS may result 3in lower medical costs.

SEOM clinical guideline on hereditary colorectal cancer (2019).

In the last 2 decades, clinical genetics on hereditary colorectal syndromes has shifted from just a molecular characterization of the different syndromes to the estimation of the individual risk of cancer and appropriate risk reduction strategies. In the last years, new specific therapies for some subgroups of patients have emerged as very effective alternatives. At the same time, germline multigene panel testing by next-generation sequencing (NGS) technology has become the new gold standard for molecular genetics.

Influence of oral anticoagulation on stroke severity and outcomes: A propensity score matching case-control study.

BACKGROUND: Oral anticoagulants (OAC) such as vitamin K antagonists (VKA) and direct-acting OACs (DOAC) remain the mainstay for prevention of cardioembolic stroke. The influence of previous OAC treatment on stroke severity and outcomes is not well stablished. We compared patients with incident cardioembolic strokes according to pre-stroke treatment. METHODS: Retrospective observational study of patients with cardioembolic stroke. Demographic data, vascular risk factors, pre-stroke treatments, reperfusion therapies and outcomes were analyzed. Propensity score matching of baseline characteristics was used to compare case-control samples across different treatment groups: adequate OAC vs no OAC; inadequate VKA vs no OAC; adequate VKA vs inadequate VKA; adequate VKA vs DOAC. RESULTS: 462 patients (76 ±â€¯11.6 years) included. 255 (55%) had a known major cardioembolic source, but only 151 (59%) of them were under OAC upon admission (127 VKA, 24 DOAC). Four patients received VKA for other reasons. Of those taking VKA, 91 (69%) had an inadequate anticoagulation. After propensity score matching, we found no significant differences in stroke severity across the different groups. Patients receiving DOAC had lower mortality at 3 months (8% vs 33%, p = .033) and higher successful recanalization rates after thrombectomy (100% vs 25%, p = .033) compared with adequate VKA anticoagulation. CONCLUSIONS: DOAC treatment significantly reduced mortality at three months compared with adequate VKA anticoagulation. Further studies are needed to confirm its influence on endovascular thrombectomy outcomes.

Características de las intoxicaciones agudas en pacientes ancianos según la edad / Characteristics of acute poisonings in elderly patients according to age

INTRODUCCIÓN: Con el aumento en la esperanza de vida, es de esperar un incremento en el número de intoxicaciones agudas en pacientes ancianos. Los objetivos del estudio son analizar las características de las intoxicaciones en >65años e identificar diferencias según la edad. METODOLOGÍA: Estudio retrospectivo comparativo en pacientes ancianos divididos en 3 grupos: 1 (66-75años), 2 (76-85años) y 3 (>85años), atendidos en Urgencias de un Hospital Universitario, por intoxicación aguda, del 2009-2014. RESULTADOS: Se recogieron 341 intoxicaciones en pacientes >65años (8,9% del total de intoxicados). Edad media: 78,9(7,7). Grupo 1: predominaron los varones (63,6% vs 28,1% y 20%; p < 0,001). Grupos 2 y 3: se intoxicaron más frecuentemente en domicilio (93,5% y 97,1% vs 58,5%; p < 0,001), de manera accidental (77,1% y 97,0% vs 34,7%; p < 0,001); mayoría por fármacos (73,9% y 85,7%) y precisaron menor contención mecánica (p < 0,006). CONCLUSIONES: Las intoxicaciones son más frecuentes en pacientes de entre 76-85 años, en los grupos 2 y 3 la mayoría son mujeres, accidentales, en domicilio y debidas a fármacos

BACKGROUND AND OBJECTIVE: With the increase in life expectancy, an increase in the number of acute poisonings in elderly patients is expected. The aims of this study are to analyze the characteristics of the poisonings in patients over 65 years and identify the differences according to age. METHODS: Comparative retrospective study in elderly patients divided into Group 1: (66-75 years), group 2: (76-85 years) and group 3: (>85 years), treated in the Emergency Department of a University Hospital for acute intoxication during a period of 6 years. RESULTS: 341 poisonings were collected in patients over 65 years (8.9% of all acute poisonings). Average age: 78.9 (7.7). In group 1, males predominated (63.6% vs. 28.1% and 20%; p <0.001). Groups 2 and 3 were more frequently intoxicated at home (93.5% and 97.1% vs. 58.5%; p <0.001), accidentally (77.1% and 97.0% vs. 34.7%; p <0.001); with greater involvement of drugs (73.9% and 85.7%) and required less mechanical containment (p <0.006). CONCLUSIONS: Poisonings are more frequent in patients between 76-85 years, in groups 2 and 3 the majority are women, accidental, at home and due to drugs

Analysis of Kidney Donation and Its Relationship With Graft Failure of the Recipient at 1 Year.

INTRODUCTION: Currently, the shortage of organs available for kidney transplantation and a change in donors' and recipients' profiles (elderly, with cardiovascular risk, donors after cardiac death), it is becoming necessary to assess grafts from expanded-criteria donors (ECD) in order to have methods that allow us to predict viability and graft survival. OBJECTIVE: The aim of this study was to analyze the different methods of renal donor assessment (estimated glomerular filtration rate [eGFR], preimplantation biopsy, and Kidney Donor Profile Index [KDPI] score) as predictors of graft survival and renal function of our recipient at 1 year. METHODS: We performed a descriptive and retrospective study of 183 deceased donor kidney transplantations performed at our center between 2011 and 2015. We calculated the KDPI scores, donor eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration Formula equation, and biopsies were evaluated using Banff classification. RESULTS: ECDs comprised 59.60%, 93% of donors had an eGFR ≥ 60 mL/min/1.73 m2, and 41% presented with a KDPI score ≥ 90%. The most frequent range in the biopsy score was 0-3. The 1-year graft survival rate was 86.90%. Factors that negatively influenced graft survival were donor/recipient age, ECD, KDPI, and cold ischemia time (CIT). CONCLUSION: Prolonged CIT and KDPI ≥ 90% were donor variables that were related to graft failure at 1 year in our center.

Total Body Water and Intracellular Water Relationships with Muscle Strength, Frailty and Functional Performance in an Elderly Population.

BACKGROUND: As a person ages, total body water (TBW), intracellular water (ICW), muscle mass and muscle strength tend to decline. The decline in ICW may reflect losses in the number of muscle cells but may also be responsible for less hydrated muscle cells. AIM: To assess whether TBW and ICW are associated with muscle strength, functional performance and frailty in an aged population, independently of muscle mass. METHODOLOGY: Design: An observational cross-sectional study of community-dwelling individuals aged 75 years and older. TBW, ICW, fat mass, lean mass and muscle mass were assessed by bioelectrical impedance analysis, frailty status was measured according to Fried criteria, handgrip strength was measured using the hand-held JAMAR dynamometer, and functional performance was measured according to the Barthel index and gait speed. RESULTS: A total of 324 subjects were recruited (mean age 80.1 years, 47.5% women). TBW and ICW were closely correlated with muscle mass in both sexes. ICW was also associated with Barthel score, gait speed and frailty in both sexes and with handgrip in men. Considerable variability in ICW was observed for the same muscle mass. Multivariate analysis showed a positive effect of ICW on handgrip, functional performance and gait speed and a protective effect of ICW on frailty, independently of age, sex, body mass index and number of comorbidities. CONCLUSIONS: In elderly individuals with similar muscle mass, those with higher ICW had a better functional performance and a lower frailty risk, suggesting a protective effect of cell hydration, independently of muscle mass.

Alpha 1 antitrypsin distribution in an allergic asthmatic population sensitized to house dust mites.

BACKGROUND AND OBJECTIVE: Severe alpha1 antitrypsin deficiency has been clearly associated with pulmonary emphysema, but its relationship with bronchial asthma remains controversial. Some deficient alpha 1 antitrypsin (AAT) genotypes seem to be associated with asthma development. The objective of this study was to analyze the distribution of AAT genotypes in asthmatic patients allergic to house dust mites (HDM), and to asses a possible association between these genotypes and severe asthma. METHODS: A cross-sectional cohort study of 648 patients with HDM allergic asthma was carried out. Demographic, clinical and analytical variables were collected. PI*S and PI*Z AAT deficient alleles of the SERPINA1 gene were assayed by real-time PCR. RESULTS: Asthma was intermittent in 253 patients and persistent in 395 patients (246 mild, 101 moderate and 48 severe). One hundred and forty-five asthmatic patients (22.4%) with at least one mutated allele (S or Z) were identified. No association between the different genotypes and asthma severity was found. No significant differences in all clinical and functional tests, as well as nasal eosinophils, IgA and IgE serum levels were observed. Peripheral eosinophils were significantly lower in patients with the PI*MS genotype (p = 0.0228). Neither association between deficient AAT genotypes or serum ATT deficiency (AATD) and development of severe asthma, or correlation between ATT levels and FEV1 was observed. CONCLUSION: In conclusion, the distribution of AAT genotypes in HDM allergic asthmatic patients did not differ from those found in Spanish population. Neither severe ATTD or deficient AAT genotypes appear to confer different clinical expression of asthma.

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action.

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1R1074H and PHF5AY36C The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5AR38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.

Brote epidémico de intoxicación alimentaria por cannabinoides / Epidemic outbreak of cannabinoid food poisoning

La marihuana es la sustancia ilícita de mayor consumo a nivel mundial. En los últimos años se han descrito casos de intoxicación por cannabinoides por vía oral, siendo su presentación habitualmente accidental. Se presenta un brote epidémico de intoxicación por cannabinoides debido a ingesta alimentaria en un establecimiento público de Barcelona. Ninguno de los afectados presentó signos de gravedad a su llegada al servicio de urgencias hospitalario. Las principales alteraciones clínicas fueron hipertensión, taquicardia, debilidad e inestabilidad cefálica. La determinación de tóxicos en orina fue positiva en todos los casos. La mayoría de los casos no requirió tratamiento farmacológico. La evolución de los pacientes fue correcta, siendo dados de alta tras unas horas de observación

Marijuana is the most consumed illicit substance worldwide. Some involuntary oral cannabinoid intoxications has been reported in recent years. An epidemic outbreak of cannabinoid intoxication due to the consumption of adulterated food in a public establishment in Barcelona is presented. None of patients showed severity signs at presentation. Hypertension, tachycardia, sickness and instability were the most frequent clinical findings. Urine drug test was positive in all cases. Patient evolution was satisfactory and all they were discharged after several hours of observation. Most cases needed no pharmacological treatment

Epidemiological study of the allergic population in the North of Gran Canaria

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