Distinguishing features of autoimmune gastritis depending on previous H. pylori infection or positivity to anti-parietal cell antibodies: results from the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO).

OBJECTIVES: To describe the clinical features and the risk of developing gastric tumors in patients with autoimmune gastritis (AIG). METHODS: This was a retrospective, longitudinal, multicenter study conducted at eight Italian tertiary referral centers. We retrieved clinical data from all histologically proven AIG patients. Differences between H. pylori-exposed vs H. pylori-naïve, and anti-parietal cell antibody (PCA)-positive vs PCA-negative patients were investigated. The rate of gastric adenocarcinoma and type 1 gastric neuroendocrine neoplasm (gNEN) was assessed. A multivariable model for factors associated to gNEN was fitted. RESULTS: 1598 patients with AIG (median age 58 years, IQR 46-68; F:M ratio 2.7:1) were included. H. pylori-naïve patients were more likely to have a first-degree family history of AIG (14.7% vs 8.9%; p=0.012), type 1 diabetes mellitus (4.9% vs 2.3%; p=0.025), and pernicious anemia (30.9% vs 21.1%; p=0.003). PCA-positive patients had significantly more associated autoimmune diseases (59.0% vs 42.9%; p<0.001) and were more likely to have been diagnosed by a case-finding strategy (15.3% vs 2.6%; p<0.001). Overall, 15 cases (0.9%) of gastric adenocarcinoma and 153 cases (9.6%) of gNEN occurred, with a global rate of 0.12 (95% CI 0.07-0.20) and 1.22 (95% CI 1.03-1.42) per 100 person/year, respectively. Having a vitamin B12/iron deficiency manifestation at AIG diagnosis was associated with an 16.44 (95% CI 9.94-27.20 p<0.001) hazard ratio of gNEN. CONCLUSIONS: The "pure" AIG pattern has typical features of an autoimmune disease and seems to be unrelated to H. pylori. In a tertiary referral setting, the risk of developing overt gastric adenocarcinoma is low, while patients with vitamin B12 deficiency complications at onset may benefit from a more intense endoscopic follow-up for early gNEN detection.

CARTAR: a comprehensive web tool for identifying potential targets in chimeric antigen receptor therapies using TCGA and GTEx data.

Chimeric antigen receptor (CAR) therapy has emerged as a ground-breaking advancement in cancer treatment, harnessing the power of engineered human immune cells to target and eliminate cancer cells. The escalating interest and investment in CAR therapy in recent years emphasize its profound significance in clinical research, positioning it as a rapidly expanding frontier in the field of personalized cancer therapies. A crucial step in CAR therapy design is choosing the right target as it determines the therapy's effectiveness, safety and specificity against cancer cells, while sparing healthy tissues. Herein, we propose a suite of tools for the identification and analysis of potential CAR targets leveraging expression data from The Cancer Genome Atlas and Genotype-Tissue Expression Project, which are implemented in CARTAR website. These tools focus on pinpointing tumor-associated antigens, ensuring target selectivity and assessing specificity to avoid off-tumor toxicities and can be used to rationally designing dual CARs. In addition, candidate target expression can be explored in cancer cell lines using the expression data for the Cancer Cell Line Encyclopedia. To our best knowledge, CARTAR is the first website dedicated to the systematic search of suitable candidate targets for CAR therapy. CARTAR is publicly accessible at https://gmxenomica.github.io/CARTAR/.

Early adversity and prosocial behavior in adolescents from Bogotá: a cross-sectional study.

BACKGROUND: The association between Adverse Childhood Experiences (ACEs), prosocial behavior, and depression (like other negative mental health outcomes) has not been thoroughly understood. This study aimed at evaluating their simultaneous association while controlling for key confounding variables. METHODS: A cross-sectional study was carried-out with 2918 secondary school students from seven charter schools located in low-resourced neighborhoods in Bogota (Colombia), 54.12% were female, and mean age was 13.81 years. The self-report instrument included demographic variables, well-being, mental health, risk behaviors and symptoms of psychopathology. Assessment of ACEs was done by a series of yes/no questions, prosocial behavior was evaluated with the corresponding subscale in the Strengths and Difficulties Questionnaire, and depression was assessed with the Self-Reporting Questionnaire. Associations were tested using the Spearman correlation coefficient, Z tests and Chi-square tests, and all primary outcome analyses were adjusted for potential confounding variables through multivariate logistic regression using depression as outcome. RESULTS: Mean exposure to ACEs was 3.15 events; those exposed to four or more obtained lower scores in well-being, satisfaction with life and family functioning, and higher scores in symptoms of psychopathology. For the prosocial behavior scores, 64.35% were classified as close to the average, 17.51% as slightly lowered, 11.91% as low, and 6.23% as very low; participants with higher levels of prosocial behavior showed lower scores in symptoms of psychopathology. While ACEs had a positive association with depressive symptoms (Odds Ratio [OR] 2.21, 95% confidence interval [CI] 1.67-2.94), prosocial behavior did not have a significant association with either ACEs or depressive symptoms in multivariate regression models. CONCLUSIONS: Novel studies should further elucidate the developmental pathways involving positive and negative mental health constructs to better understand the actual effectiveness of interventions that use these constructs in their design.

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits and minimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring. This paper aims to investigate the potentiality of coupling RL with population PK/PD models to develop precision dosing algorithms, reviewing the most relevant works in the field. Case studies in which PK/PD models were integrated within RL algorithms as simulation engine to predict consequences of any dosing action have been considered and discussed. They mainly concern propofol-induced anesthesia, anticoagulant therapy with warfarin and a variety of anticancer treatments differing for administered agents and/or monitored biomarkers. The resulted picture highlights a certain heterogeneity in terms of precision dosing approaches, applied methodologies, and degree of adherence to the clinical domain. In addition, a tutorial on how a precision dosing problem should be formulated in terms of the key elements composing the RL framework (i.e., system state, agent actions and reward function), and on how PK/PD models could enhance RL approaches is proposed for readers interested in delving in this field. Overall, the integration of PK/PD models into a RL-framework holds great promise for precision dosing, but further investigations and advancements are still needed to address current limitations and extend the applicability of this methodology to drugs requiring adaptive dosing strategies.

Predicting ADMET Properties from Molecule SMILE: A Bottom-Up Approach Using Attention-Based Graph Neural Networks.

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline.

Further Validation of the Persecutory Ideation Questionnaire in the Italian Context: Results From Classical and Modern Test Theory.

The Persecutory Ideation Questionnaire (PIQ) is a valuable instrument to measure persecutory ideation. The aim of this study is to validate the scale in the Italian context and to extend the study of its psychometric properties using approaches from both classical and modern test theories. The results of the study, involving 700 individuals, confirmed the one-factor structure and the good validity and reliability of the scale. Full metric invariance and partial scalar and strict invariance were also supported across gender, age, and education level groups. Rasch analysis indicated that the 5-point response scale is well-functioning and that the PIQ is most appropriate to measure high levels of persecutory ideation. The results contribute to a better understanding of the measurement properties of the PIQ. The paper discusses the advantages and contributions of each method used to explore the measurement properties of the scale.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.

MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.

Physico-chemical characterization and possible uses of sludge processed from an urban sewage treatment plant.

Nowadays, the challenge is to transform dehydrated sewage sludge resulting from wastewater treatment plants from waste into resource. Following this objective, the sludge was further dried and submitted to X-ray diffraction (XRD) and FTIR analysis. The sludge was first dried in ventilated and unventilated spaces at 50 ∘C and 100 ∘C, for 60 and 100 minutes (min) in each case. The final mass and evaporation degree of the sludge depends on the initial mass, ventilation type, drying time, and temperature. The ventilated drying space is preferred for temperature control, homogeneity, and higher evaporation degree. The influence of the drying process on the structure and behavior of the sewage sludge was emphasized through X-ray diffraction (XRD) and FTIR analysis. The XRD shows good structural properties of the sludge samples given by the reduction of the particle size through evaporation. According to FTIR, evaporation influences the depolymerization of the silicate network. The hydroxyl units and metallic ion modifiers can improve the sludge structure, but its intensity decreases through evaporation. With high content of solid substance, and good relation between the composition of the sludge and its structure and behavior, the dried sewage sludge can be used in: (i) agriculture, (ii) construction, (iii) the energy sector.

Visual statistical learning in preverbal infants at a higher likelihood of autism and its association with later social communication skills.

Visual statistical Learning (SL) allows infants to extract the statistical relationships embedded in a sequence of elements. SL plays a crucial role in language and communication competencies and has been found to be impacted in Autism Spectrum Disorder (ASD). This study aims to investigate visual SL in infants at higher likelihood of developing ASD (HL-ASD) and its predictive value on autistic-related traits at 24-36 months. At 6 months of age, SL was tested using a visual habituation task in HL-ASD and neurotypical (NT) infants. All infants were habituated to a visual sequence of shapes containing statistically predictable patterns. In the test phase, infants viewed the statistically structured, familiar sequence in alternation with a novel sequence that did not contain any statistical information. HL-ASD infants were then evaluated at 24-36 months to investigate the associations between visual SL and ASD-related traits. Our results showed that NT infants were able to learn the statistical structure embedded in the visual sequences, while HL-ASD infants showed different learning patterns. A regression analysis revealed that SL ability in 6-month-old HL-ASD infants was related to social communication and interaction abilities at 24-36 months of age. These findings indicate that early differences in learning visual statistical patterns might contribute to later social communication skills.

Human leukocyte antigen variants associate with BNT162b2 mRNA vaccine response.

BACKGROUND: Since the beginning of the anti-COVID-19 vaccination campaign, it has become evident that vaccinated subjects exhibit considerable inter-individual variability in the response to the vaccine that could be partly explained by host genetic factors. A recent study reported that the immune response elicited by the Oxford-AstraZeneca vaccine in individuals from the United Kingdom was influenced by a specific allele of the human leukocyte antigen gene HLA-DQB1. METHODS: We carried out a genome-wide association study to investigate the genetic determinants of the antibody response to the Pfizer-BioNTech vaccine in an Italian cohort of 1351 subjects recruited in three centers. Linear regressions between normalized antibody levels and genotypes of more than 7 million variants was performed, using sex, age, centers, days between vaccination boost and serological test, and five principal components as covariates. We also analyzed the association between normalized antibody levels and 204 HLA alleles, with the same covariates as above. RESULTS: Our study confirms the involvement of the HLA locus and shows significant associations with variants in HLA-A, HLA-DQA1, and HLA-DQB1 genes. In particular, the HLA-A*03:01 allele is the most significantly associated with serum levels of anti-SARS-CoV-2 antibodies. Other alleles, from both major histocompatibility complex class I and II are significantly associated with antibody levels. CONCLUSIONS: These results support the hypothesis that HLA genes modulate the response to Pfizer-BioNTech vaccine and highlight the need for genetic studies in diverse populations and for functional studies aimed to elucidate the relationship between HLA-A*03:01 and CD8+ cell response upon Pfizer-BioNTech vaccination.

It is known that people respond differently to vaccines. It has been proposed that differences in their genes might play a role. We studied the individual genetic makeup of 1351 people from Italy to see if there was a link between their genes and how well they responded to the BNT162b2 mRNA COVID-19 vaccine. We discovered certain genetic differences linked to higher levels of protection in those who got the vaccine. Our findings suggest that individual's genetic characteristics play a role in vaccine response. A larger population involving diverse ethnic backgrounds will need to be studied to confirm the generalizability of these findings. Better understanding of this could facilitate improved vaccine designs against new SARS-CoV-2 variants.

A bioclimatic evaluation of sustainable tourist activities in western Romania.

The study analyzes with priority the bioclimatic conditions for tourist activities in two famous tourist areas in western Romania [(Baile Felix-Baile 1 Mai (BF_1 M) - Stâna de Vale - Vladeasa and, respectively Baile Herculane (BH) - Semenic], from the perspective of the potential of health tourism and in the subsidiary of sports and camping tourism. Such researches are missing for western Romania. The main working tools in the evaluation of the tourist valences of the bioclimate include: the spatio-temporal analysis of the Physiologically Equivalent Temperature (PET) bioclimatic index, of the TCI climate-tourism index and of the climate-tourism schemes (CTIS). PET, TCI and CTIS were calculated and drawn up based on the daily data of the meteorological elements included in their calculation for the period 1961-2019. The bioclimate is analyzed as an element of potential that can increase (through a better evaluation and knowledge) the attractiveness and sustainability of the health tourism in the already established resorts (BF_1 M, BH) and can develop sports and camping tourism in the direction of the two proposed axes (Stâna de Vale - Vladeasa și Semenic), with the decongestion of the resorts from the base the mountains. The proposed objectives consist inmulti-criteria evaluation, promotion and sustainable exploitation of the bioclimatic (and spa) resources of the six tourist destinations, but it also aims to increase the level of attention and information of all those interested, by promoting the bioclimatic and climate-tourism assets of complementary tourist destinations (Stâna de Vale, Vladeasa, Semenic). The results obtained from the PET statistics show that between 25 and 39 % of the days of a year are comfortable, and the TCI statistics show that between 54 and 69 % of the days are favorable for the practice of tourism. PET and TCI highlight that from mid-April to mid-October the bioclimatic conditions for health tourism are good at BF_1 M and BH and that, only in the months of December-February the balneoclimatic procedures carried out outside the treatment bases are subject to climatic restrictions. Sports tourism has few temporal restrictions, and camping tourism restricts its duration, from April to October in lowland resorts, to May to September in mountain tourist destinations. CTIS shows that the resorts in western Romania have the most favorable bioclimatic and climate-tourism conditions in Romania.

Diagnostic Contexts of Echocardiographic Nonapical Window.

The long-established utility of multiwindow interrogation in echocardiography (suprasternal notch, right and left sternal border, apex, and subxiphoid) is sometimes not systematically implemented in routine practice. This case series emphasizes the pivotal importance of such practice for the systematic assessment of aortic valve stenosis and in the evaluation of left ventricular outflow tract and the aorta.

Where Morphological and Molecular Classifications Meet: The Role of p53 Immunohistochemistry in the Prognosis of Low-Risk Endometrial Carcinoma (GLAMOUR Study).

No prospective study has validated molecular classification to guide adjuvant treatment in endometrial cancer (EC), and not even retrospective data are present for patients with morphological low-risk EC. We conducted a retrospective, multicenter, observational study including 370 patients with low-risk endometrioid EC to evaluate the incidence and prognostic role of p53 abnormal expression (p53abn) in this specific subgroup. Among 370 patients, 18 had abnormal expressions of p53 (4.9%). In 13 out of 370 patients (3.6%), recurrences were observed and two were p53abn. When adjusting for median follow-up time, the odds ratio (OR) for recurrence among those with p53abn versus p53 wild type (p53wt) was 5.23-CI 95% 0.98-27.95, p = 0.053. The most common site of recurrence was the vaginal cuff (46.2%). One recurrence occurred within the first year of follow-up, and the patient exhibited p53abn. Both 1-year and 2-year DFS rates were 94.4% and 100% in the p53abn and p53wt groups, respectively. One patient died from the disease and comprised p53wt. No difference in OS was registered between the two groups; the median OS was 21.9 months (16.4-30.1). Larger multicenter studies are needed to tailor the treatment of low-risk EC patients with p53abn. Performing molecular classification on all EC patients might be cost-effective, and despite the limits of our relatively small sample, p53abn patients seem to be at greater risk of recurrence, especially locally and after two years since diagnosis.

Prevalencia de caídas en pacientes ingresados en un hospital universitario / Prevalence of falls in patients admitted to a University Hospital

Objetivo: analizar la prevalencia de caídas de los pacientes hos­pitalizados en un hospital universitario, así como los factores asociados con la asistencia sanitaria (motivos de las caídas, especialidad más prevalente, turno más frecuente, si estaban solos o acompañados, etc.) en los pacientes que se cayeron y las posibles consecuencias de las caídas. Métodos: estudio transversal. Se incluyeron a todos los pacientes adultos ingresados en 20 unidades de hospitalización del Hospital Universitario de Burgos, que habían sufrido una caída en 2019 y estaban incluidos en el registro de caídas del programa GACELA Care®. El formulario consta de 28 campos de en­trada de datos, que aportan información relevante sobre la caída. Se llevó a cabo análisis descriptivo y comparativo, usando los test estadísticos correspondientes. Resultados: se registraron 244 caídas (0,9%). La edad media fue 73,3 años. El 54,4% tenía edad igual o mayor a 75 años. El 57,8% era del sexo masculino. En Medicina Interna (29,1%) y Psiquiatría (11,1%) se registró el mayor porcentaje de caídas. El 44,2% se produjo en turno de noche, en pacientes que estaban solos (71,7%), sin protecciones (70,5%); y deambulando (36,1%). El motivo principal fue la inestabilidad motora (48,4%). El 62,7% de los pacientes resultó ileso. La especialidad y el turno de trabajo se asociaron significativamente con las caídas. Conclusiones: la prevalencia de caídas en el hospital fue baja. Los factores que se relacionaron con mayor porcentaje de caídas fueron ser mayor de 75 años, sexo masculino, estar ingresado en unidades de especialidad médica y turno de noche. Las caídas ocurrieron habitualmente cuando el paciente estaba solo, sin protección, al levantarse y caminar. La mayoría de los pacientes no presentó lesiones.(AU)

Objective: to analyse the prevalence of falls in patients admitted to a University Hospital, as well as to identify the characteristics of those patients who experienced falls, the factors associated with patient care (reasons for falls, the most prevalent specialty, the most frequent shift, whether they were alone or accompanied, etc.) among patients who fell down, and the potential consequences of said falls. Methods: a cross-sectional study, including all adult patients admitted to 20 hospitalization units from the Hospital Universitario de Burgos, who had experienced a fall in 2019 and were included in the register of falls from the GACELA Care® program. The form consisted of 28 data entry fields, and included information about date, time and place of the fall; reasons for falls; consequences of falls, and action by professionals. Descriptive and comparative analysis was conducted, using the relevant statistical tests. Results: in total, 244 (0.9%) falls were registered. The mean age was 73.3 years; 57.8% were male. The highest proportion of falls was recorded at Internal Medicine (29.1%) and Psychiatry (11.1%); 44.2% occurred during the night shift, in patients who were alone (71.7%); without protections (70.5%); and walking around (36.1%). The main reason was motor instability (48,4%); 62.7% of patients remained unharmed. There was a significant association between specialty and work shift and falls. Conclusions: there was a low prevalence of falls in the hospital. The factors associated with a higher proportion of falls were being >75-year-old, male gender, being admitted to medical specialty units, and night shift. Falls commonly occurred when the patient was alone, without protection, when getting up and walking. Most patients did not present any lesions.(AU)

HIV-Related Oral Mucosa Lesions: A Cross-Sectional Study on a Cohort of Italian Patients.

BACKGROUND: Human immunodeficiency virus (HIV) infection can be associated with oral mucosal diseases, including oral candidiasis and HPV infection, which are putative indicators of the immune status. AIM AND METHODS: This retrospective cross-sectional study was aimed at assessing the prevalence of HIV-related oral mucosal lesions in a cohort of Italian HIV+ patients regularly attending the Clinics of Infectious Diseases. RESULTS: One hundred seventy-seven (n = 177) patients were enrolled and 30 (16.9%) of them showed HIV-related diseases of the oral mucosa. They were mainly found in male patients over 35 years old, undergoing Combination Antiretroviral Therapy (cART), and with CD4+ count < 500/µL. Oral candidiasis was the most common HIV-related oral lesion. No significant correlations could be detected between the prevalence of HPV infection and other clinical parameters (lymphocyte count, cART treatment and viral load). CONCLUSIONS: HIV-related oral mucosal diseases can correlate with immunosuppression. Early diagnosis and management of oral lesions in HIV+ patients should be part of the regular follow-up, from a multidisciplinary perspective of collaboration between oral medicine and infectious disease specialists, in an attempt to reduce morbidity due to oral lesions and modulate antiretroviral therapy according to the patient's immune status.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Implementing Enhanced Recovery After Surgery for hysterectomy in a hospital network with audit and feedback: A stepped-wedge cluster randomised trial.

OBJECTIVE: To evaluate the effectiveness of implementing the Enhanced Recovery After Surgery (ERAS) protocol in patients undergoing elective hysterectomy in a network of regional hospitals, supported by an intensive audit-and-feedback (A&F) approach. DESIGN: A multi-centre, stepped-wedge cluster randomised trial (ClinicalTrials.gov NCT04063072). SETTING: Gynaecological units in the Piemonte region, Italy. POPULATION: Patients undergoing elective hysterectomy, either for cancer or for benign conditions. METHODS: Twenty-three units (clusters), stratified by surgical volume, were randomised into four sequences. At baseline (first 3 months), standard care was continued in all units. Subsequently, the four sequences implemented the ERAS protocol successively every 3 months, after specific training. By the end of the study, each unit had a period in which standard care was maintained (control) and a period in which the protocol, supported by feedback, was applied (experimental). MAIN OUTCOME MEASURES: Length of hospital stay (LOS), without outliers (>98th percentile). RESULTS: Between September 2019 and May 2021, 2086 patients were included in the main analysis with an intention-to-treat approach: 1104 (53%) in the control period and 982 (47%) in the ERAS period. Compliance with the ERAS protocol increased from 60% in the control period to 76% in the experimental period, with an adjusted absolute difference of +13.3% (95% CI 11.6% to 15.0%). LOS, moving from 3.5 to 3.2 days, did not show a significant reduction (-0.12 days; 95% CI -0.30 to 0.07 days). No difference was observed in the occurrence of complications. CONCLUSIONS: Implementation of the ERAS protocol for hysterectomy at the regional level, supported by an A&F approach, resulted in a substantial improvement in compliance, but without meaningful effects on LOS and complications. This study confirms the effectiveness of A&F in promoting important innovations in an entire hospital network and suggests the need of a higher compliance with the ERAS protocol to obtain valuable improvements in clinical outcomes.

Reinforcement Learning and PK-PD Models Integration to Personalize the Adaptive Dosing Protocol of Erdafitinib in Patients with Metastatic Urothelial Carcinoma.

The integration of pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations with artificial intelligence/machine learning algorithms is one of the most attractive areas of the pharmacometric research. These hybrid techniques are currently under investigation to perform several tasks, among which precision dosing. In this scenario, this paper presents and evaluates a new framework embedding PK-PD models into a reinforcement learning (RL) algorithm, Q-learning (QL), to personalize pharmacological treatment. Each patient is represented with a set of PK-PD parameters and has a personal QL agent which optimizes the individual treatment. In the training phase, leveraging PK-PD simulations, the QL agent assesses different actions, defined consistently with the clinical knowledge to consider only plausible dose-adjustments, in order to find the optimal rules. The proposed framework was evaluated to optimize the erdafitinib treatment in patients with metastatic urothelial carcinoma. This drug was approved by the US Food and Drug Administration (FDA) with a dose-adaptive protocol based on monitoring the levels of serum phosphate, which represent a biomarker of both treatment efficacy and toxicity. To evaluate the flexibility of the methodology, a heterogeneous virtual population of 141 patients was generated using an erdafitinib population PK (PopPK)-PD literature model. For each patient, treatment response was simulated by using both QL-optimized protocol and the clinical one. QL agents outperform the approved dose-adaptive rules, increasing more than 10% the efficacy and the safety of treatment at each end point. Results confirm the great potentialities of the integration of PopPK-PD models and RL algorithms to optimize precision dosing tasks.