SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.

Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.

Muscle mass loss measured with portable ultrasound in hospitalized older adults: The ECOSARC study.

OBJECTIVES: The main objective was to analyze the evolution of muscle of the Quadriceps Rectus Femoris (QRF) between admission and discharge, in older adults hospitalized with an acute medical disease in Acute Geriatric Units (AGUs). DESIGN: Prospective multicentric observational cohort study. SETTING: Seven AGUs from University Hospitals in Spain. PARTICIPANTS: Hospitalized adults ≥ 70 years old, able to ambulate and without severe dementia. MEASUREMENTS: Ultrasound measurements of QRF were acquired at 2/3 distal between anterior-superior iliac spine and patella in both legs by trained Geriatricians. Ultrasound Chison model ECO2 was used. QRF area, thickness, edema, echogenicity, and fasciculations were measured. RESULTS: From the complete sample (n = 143), in 45 (31.5%) participants, ultrasound images were classified as non-valid by an expert radiologist. Mean age was 87.8 (SD 5.4). Mean hospital stay 7.6 days (SD 4.3). From those with valid images, 36 (49.3%), 2 (2.7%), and 35 (47.9%) presented a decrease, equal values, or an increase in QRF area from baseline to discharge, respectively, and 37 (50.0%), 2 (2.7%), and 35 (47.3%) presented a decrease, equal values, or an increase in QRF thickness, respectively. 26 (35.6%) presented a decrease in more than 0.2 cm2 of QRF area, and 23 (31.1%) a decrease in more than 0.1 cm of QRF thickness. Only 4 (5.4%) patients presented new edema, while 13 (17.6%) worsened echogenicity. CONCLUSION: One third of older adults develop significant muscle loss during a hospitalization for acute medical diseases. TRIAL REGISTRATION NUMBER: NCT05113758.

Long-term outcomes of an educational paediatric antimicrobial stewardship programme: a quality improvement study.

BACKGROUND AND OBJECTIVES: Antimicrobial stewardship programmes (ASPs) have resulted in antimicrobial consumption (AMC) reduction and quality of prescription (QOP) improvement. However, evidence of ASP impact in paediatrics is still limited. This study aims to assess a paediatric ASP long-term outcomes. METHODS: A quality improvement study assessed by a interrupted time series analysis was conducted in a paediatric tertiary hospital. QOP expressed as proportion of adequate prescriptions, AMC measured by defined daily dose incidence per 1000 occupied bed days, incidence density of bloodstream infections (BSIs) and its related all-cause crude death rate (CDR) were compared between pre (from January 2013 to December 2015) and post (from January 2016 to December 2019) ASP activities intensification, which included a dedicated paediatric infectious diseases physician to actively perform educational interviews with prescribers. RESULTS: Inappropriate prescribing showed a significant downward shift associated to the intervention with a -51.4% (-61.2% to -41.8%) reduction with respect to the expected values. Overall AMC showed no trend change after the intervention. For neonatology a28.8% (-36.8% to -20.9%) reduction was observed. Overall anti-pseudomonal cephalosporin use showed a -51.2% (-57.0% to -45.4%) reduction. Decreasing trends were observed for carbapenem use, with a quarterly per cent change (QPC) of -2.4% (-4.3% to -0.4%) and BSI-related CDR (QPC=-3.6%; -5.4% to -1.7%) through the study period. Healthcare-associated multi-drug-resistant BSI remained stable (QPC=2.1; -0.6 to 4.9). CONCLUSIONS: Intensification of counselling educational activities within an ASP suggests to improve QOP and to partially reduce AMC in paediatric patients. The decreasing trends in mortality remained unchanged.

Towards the automated detection of interictal epileptiform discharges with magnetoencephalography.

BACKGROUND: The analysis of clinical magnetoencephalography (MEG) in patients with epilepsy traditionally relies on visual identification of interictal epileptiform discharges (IEDs), which is time consuming and dependent on subjective criteria. NEW METHOD: Here, we explore the ability of Independent Components Analysis (ICA) and Hidden Markov Modeling (HMM) to automatically detect and localize IEDs. We tested our pipelines on resting-state MEG recordings from 10 school-aged children with (multi)focal epilepsy. RESULTS: In focal epilepsy patients, both pipelines successfully detected visually identified IEDs, but also revealed unidentified low-amplitude IEDs. Success was more mitigated in patients with multifocal epilepsy, as our automated pipeline missed IED activity associated with some foci-an issue that could be alleviated by post-hoc manual selection of epileptiform ICs or HMM states. COMPARISON WITH EXISTING METHODS: We compared our results with visual IED detection by an experienced clinical magnetoencephalographer, getting heightened sensitivity and requiring minimal input from clinical practitioners. CONCLUSIONS: IED detection based on ICA or HMM represents an efficient way to identify IED localization and timing. The development of these automatic IED detection algorithms provide a step forward in clinical MEG practice by decreasing the duration of MEG analysis and enhancing its sensitivity.

Implementation of a PCR-based strategy to control an outbreak by Serratia marcescens in a Neonatal Intensive Care Unit.

OBJECTIVES: To evaluate the clinical and epidemiological impact of a new molecular surveillance strategy based on qPCR to control an outbreak by Serratia marcescens in a Neonatal Intensive Care Unit (NICU). METHODS: We design a specific qPCR for the detection of S. marcescens in rectal swabs of patients admitted to a NICU. We divided the surveillance study into two periods: (a) the pre-PCR, from the outbreak declaration to the qPCR introduction, and (b) the PCR period, from the introduction of the qPCR until the outbreak was solved. In all cases, S. marcescens isolates were recovered and their clonal relationship was analysed by PFGE. Control measures were implemented during the outbreak. Finally, the number of bloodstream infections (BSI) was investigated in order to evaluate the clinical impact of this molecular strategy. RESULTS: Nineteen patients colonized/infected by S. marcescens were detected in the pre-PCR period (October 2020-April 2021). On the contrary, after the PCR implementation, 16 new patients were detected. The PFGE revealed 24 different pulsotypes belonging to 7 different clonal groups, that were not overlapping at the same time. Regarding the clinical impact, 18 months after the qPCR implementation, no more outbreaks by S. marcescens have been declared in the NICU of our hospital, and only 1 episode of BSI has occurred, compared with 11 BSI episodes declared previously to the outbreak control. CONCLUSIONS: The implementation of this qPCR strategy has proved to be a useful tool to control the nosocomial spread of S. marcescens in the NICU.

Addressing Gendered Racism Against Black Girls Using a Strengths-Based Empowerment-Intersectional Framework for Sexual Health and Substance Use Prevention Programming.

Although Black girls use substances at lower rates than boys and girls from various other racial groups, they tend to have worse health outcomes associated with substance use that can also impact their sexual health. The association between substance use and sexual risk behaviors is usually attributed to lack of access to quality health care and lack of culturally specific prevention programming and treatment options tailored to this group. Accordingly, the theoretical frameworks for health promotion for Black girls often focus on addressing deficits, ignoring the powerful and intersecting social forces that can impact identity, agency, and behavioral options. Key among these forces is gendered racism. We propose a strengths-based conceptual framework to address and challenge gendered racism as a critical foundation for promoting health and wellbeing for Black girls. Our approach integrates Intersectionality Theory and Empowerment Theory, with psychological and intrapersonal empowerment identified as critical mediators of behavior and health outcomes, supported by protective factors of positive racial identity and gendered racial socialization. This framework has been developed with and for Black girls but can be adapted for health promotion efforts with other minoritized groups.

"SARCOPENIA MEASURED BY ULTRASOUND IN HOSPITALIZED OLDER ADULTS" (ECOSARC): multi-centre, prospective observational study protocol.

BACKGROUND: Measurement of muscle mass and function, and thereafter, screening and diagnosis of sarcopenia, is a challenge and a need in hospitalized older adults. However, it is difficult in complex real-world old patients, because usually they are unable to collaborate with clinical, functional, and imaging testing. Ultrasound measurement of quadriceps rectus femoris (QRF) provides a non-invasive, real-time assessment of muscle quantity and quality, and is highly acceptable to participants with excellent inter-rater and intra-rater variability. However, normative data, protocol standardization, and association with longitudinal outcomes, needs further research and consensus. METHODS: Prospective exploratory multicenter study in older adults admitted to Acute Geriatric Units (AGUs) for medical reasons. 157 subjects from 7 AGUs of Spain were recruited between May 2019 and January 2022. Muscle ultrasound measurements of the anterior vastus of the QRF were acquired on admission and on discharge, using a previously validated protocol, using a Chieson model ECO2 ultrasound system (Chieson Medical Technologies, Co. Ltd, Wimxu District Wuxi, Jiangsu, China). Measurements included the cross-sectional area, muscle thickness in longitudinal view, intramuscular central tendon thickness, echogenicity, and the presence or absence of edema and fasciculations. Functional, nutritional, and DXA measurements were provided. Clinical follow-up was completed at discharge, and 30 and 90 days after discharge. Variations between hospital admission and discharge ultrasound values, and the relationship with clinical variables, will be analyzed using paired t-tests, Wilcoxon tests, or Mc Nemar chi-square tests when necessary. Prevalence of sarcopenia will be calculated, as well as sensitivity and specificity of ultrasound measurements to determine sarcopenia. Kappa analysis will be used to analyze the concordance between measurements, and sensitivity analysis will be conducted for each participating center. DISCUSSION: The results obtained will be of great interest to the scientific geriatric community to assess the utility and validity of ultrasound measurements for the detection and follow-up of sarcopenia in hospitalized older adults, and its association with adverse outcomes. TRIAL REGISTRATION: NCT05113758. Registration date: November 9th 2021. Retrospectively registered.

Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial.

OBJECTIVE: We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. DESIGN: A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. RESULTS: Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. CONCLUSION: For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. TRIAL REGISTRATION NUMBER: NCT01884415.

Psychometric Testing of the CEECCA Questionnaire to Assess Ability to Communicate among Individuals with Aphasia.

(1) Background: The CEECCA questionnaire assesses the ability to communicate among individuals with aphasia. It was designed using the NANDA-I and NOC standardised nursing languages (SNLs), reaching high content validity index and representativeness index values. The questionnaire was pilot-tested, demonstrating its feasibility for use by nurses in any healthcare setting. This study aims to identify the psychometric properties of this instrument. (2) Methods: 47 individuals with aphasia were recruited from primary and specialist care facilities. The instrument was tested for construct validity and criterion validity, reliability, internal consistency, and responsiveness. The NANDA-I and NOC SNLs and the Boston test were used for criterion validity testing. (3) Results: five language dimensions explained 78.6% of the total variance. Convergent criterion validity tests showed concordances of up to 94% (Cohen's κ: 0.9; p < 0.001) using the Boston test, concordances of up to 81% using DCs of NANDA-I diagnoses (Cohen's κ: 0.6; p < 0.001), and concordances of up to 96% (Cohen's κ: 0.9; p < 0.001) using NOC indicators. The internal consistency (Cronbach's alpha) was 0.98. Reliability tests revealed test-retest concordances of 76-100% (p < 0.001). (4) Conclusions: the CEECCA is an easy-to-use, valid, and reliable instrument to assess the ability to communicate among individuals with aphasia.

Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability.

Homologous recombination (HR) plays an essential role in the maintenance of genome stability by promoting the repair of cytotoxic DNA double strand breaks (DSBs). More recently, the HR pathway has emerged as a core component of the response to replication stress, in part by protecting stalled replication forks from nucleolytic degradation. In that regard, the mammalian RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have been involved in both HR-mediated DNA repair and collapsed replication fork resolution. Still, it remains largely obscure how they participate in both processes, thereby maintaining genome stability and preventing cancer development. To gain better insight into their contribution in cellulo, we mapped the proximal interactome of the classical RAD51 paralogs using the BioID approach. Aside from identifying the well-established BCDX2 and CX3 sub-complexes, the spliceosome machinery emerged as an integral component of our proximal mapping, suggesting a crosstalk between this pathway and the RAD51 paralogs. Furthermore, we noticed that factors involved RNA metabolic pathways are significantly modulated within the BioID of the classical RAD51 paralogs upon exposure to hydroxyurea (HU), pointing towards a direct contribution of RNA processing during replication stress. Importantly, several members of these pathways have prognostic potential in breast cancer (BC), where their RNA expression correlates with poorer patient outcome. Collectively, this study uncovers novel functionally relevant partners of the different RAD51 paralogs in the maintenance of genome stability that could be used as biomarkers for the prognosis of BC.

[Post-vaccination antibodies against SARS-CoV-2 in a cohort of workers of a general hospital]. / Anticuerpos postvacunales frente a SARS-CoV-2 en una cohorte de trabajadores de un hospital general.

INTRODUCTION: The aim was to estimate the evolution of the levels of anti-SARS-CoV-2 antibodies, the associated factors, and the incidence of new infections during the follow-up period.  Method: Prospective cohort study of a representative sample of workers at the General University Hospital of Castellon 8 months after receiving the second dose of Pfizer-BioNTech vaccine against SARS-CoV-2, by determining IgG-S, IgG-NP, follow-up and response to a questionnaire. The results were compared with those at the start of the cohort in February 2021. Multivariate linear regression and Poisson regression were used.  Results: A total of 253 workers participated out of the 275 in the start of the cohort. All had detectable levels of IgG-S, median 691% AU/ml, decreasing by 93.3% compared with the first study. The decline of IgG-S increased with age and obesity; and decreased with a COVID-19 previous history, regular exercise, and in smokers. IgG-NP was positively associated with a history of COVID-19, taking vitamin D, and decreased from 4.4% to 1.2%. There were 4 new cases of COVID-19 in the cohort, with and incidence rate of 1.7%. One death occurred in a participant with immunosuppressive treatment, only one case was asymptomatic and no reinfections occurred. CONCLUSIONS: A general decrease of IgG-S and IgG-NP antibodies after the second dose of Pfizer-BioNTech vaccine was observed in the cohort, as well as with new SARS-CoV-2 infections. Booster doses, maintaining protective measures and further determination of the protection threshold of vaccination are recommended.

Introducción: Estimar la evolución de los niveles de anticuerpos anti-SARS-CoV-2 y los factores asociados, así como la incidencia de nuevas infecciones. Método: Estudio de cohorte prospectivo de una muestra representativa de trabajadores del Hospital General Universitario de Castellón a los 8 meses de recibir la 2ª dosis de la vacuna Pfizer-BioNTech contra el SARS-CoV-2, mediante la determinación de anticuerpos IgG-S y IgG-NP, y la cumplimentación de un cuestionario. Se compararon los resultados con los del inicio de la cohorte en febrero de 2021. Se usó regresión lineal múltiple y regresión de Poisson.  Resultados: Participaron 253 trabajadores de los 275 reclutados al inicio de la cohorte (92%). Todos mantenían niveles detectables de IgG-S, mediana de 691,5 UA/ml, disminuyendo un 93,3% con respecto al inicio. Los descensos de IgG-S fueron mayores con la edad y la obesidad, y menores en aquellos con historia de COVID-19, IgG-S elevada inicial, practicar ejercicio habitual y ser fumador. Tener IgG-NP se asoció positivamente con historia de COVID-19, tomar vitamina D, y disminuyeron del 4,4% al 1,2%. Se produjeron 4 casos de COVID-19 en la cohorte, con una tasa de incidencia del 1,7%, con un fallecimiento en un participante con tratamiento inmunosupresor, solo un caso fue asintomático y no hubo reinfecciones.  Conclusiones: Se produce un descenso general de los anticuerpos IgG-S e IgG-NP después de la segunda dosis de vacuna Pfizer-BioNTech, así como nuevas infecciones por SARS-CoV-2. Se recomienda dosis de recuerdo, mantener medidas protectoras y determinar el umbral de anticuerpos protectores de la vacunación.