Profiling heart failure with preserved or mildly reduced ejection fraction by cluster analysis.

BACKGROUND: Significant knowledge gaps remain regarding the heterogeneity of heart failure (HF) phenotypes, particularly among patients with preserved or mildly reduced left ventricular ejection fraction (HFp/mrEF). Our aim was to identify HF subtypes within the HFp/mrEF population. METHODS: K-prototypes clustering algorithm was used to identify different HF phenotypes in a cohort of 2 570 patients diagnosed with HFmrEF or HFpEF. This algorithm employs the k-means algorithm for quantitative variables and k-modes for qualitative variables. RESULTS: We identified three distinct phenotypic clusters: Cluster A (n = 850, 33.1%), characterized by a predominance of women with low comorbidity burden; Cluster B (n = 830, 32.3%), mainly women with diabetes mellitus and high comorbidity; and Cluster C (n = 890, 34.5%), primarily men with a history of active smoking and respiratory comorbidities. Significant differences were observed in baseline characteristics and one-year mortality rates across the clusters: 18% for Cluster A, 33% for Cluster B, and 26.4% for Cluster C (P < 0.001). Cluster B had the shortest median time to death (90 days), followed by Clusters C (99 days) and A (144 days) (P < 0.001). Stratified Cox regression analysis identified age, cancer, respiratory failure, and laboratory parameters as predictors of mortality. CONCLUSION: Cluster analysis identified three distinct phenotypes within the HFp/mrEF population, highlighting significant heterogeneity in clinical profiles and prognostic implications. Women were classified into two distinct phenotypes: low-risk women and diabetic women with high mortality rates, while men had a more uniform profile with a higher prevalence of respiratory disease.

Parkinson's Disease Gene Screening in Familial Cases from Central and South America.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease following Alzheimer's disease. Nearly 30 causative genes have been identified for PD and related disorders. However, most of these genes were identified in European-derived families, and little is known about their role in Latin American populations. OBJECTIVES: Our goal was to assess the spectrum and frequency of pathogenic variants in known PD genes in familial PD patients from Latin America. METHODS: We selected 335 PD patients with a family history of PD from the Latin American Research Consortium on the Genetics of PD. We capture-sequenced the coding regions of 26 genes related to neurodegenerative parkinsonism. Of the 335 PD patients, 324 had sufficient sequencing coverage to be analyzed. RESULTS: We identified pathogenic variants in 41 individuals (12.7%) in FBXO7, GCH1, LRRK2, PARK7, PINK1, PLA2G6, PRKN, SNCA, and TARDBP, GBA1 risk variants in 25 individuals (7.7%), and variants of uncertain significance in another 24 individuals (7.4%) in ATP13A2, ATP1A3, DNAJC13, DNAJC6, GBA1, LRKK2, PINK1, VPS13C, and VPS35. Of the 70 unique variants identified, 19 were more frequent in Latin Americans than in any other population. CONCLUSIONS: This is the first screening of known PD genes in a large cohort of patients with familial PD from Latin America. There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European-derived populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long Non-Coding RNAs and Alzheimer's Disease: Towards Personalized Diagnosis.

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, is the most common form of dementia. Currently, there is no single test that can diagnose AD, especially in understudied populations and developing countries. Instead, diagnosis is based on a combination of medical history, physical examination, cognitive testing, and brain imaging. Exosomes are extracellular nanovesicles, primarily composed of RNA, that participate in physiological processes related to AD pathogenesis such as cell proliferation, immune response, and neuronal and cardiovascular function. However, the identification and understanding of the potential role of long non-coding RNAs (lncRNAs) in AD diagnosis remain largely unexplored. Here, we clinically, cognitively, and genetically characterized a sample of 15 individuals diagnosed with AD (cases) and 15 controls from Barranquilla, Colombia. Advanced bioinformatics, analytics and Machine Learning (ML) techniques were used to identify lncRNAs differentially expressed between cases and controls. The expression of 28,909 lncRNAs was quantified. Of these, 18 were found to be differentially expressed and harbored in pivotal genes related to AD. Two lncRNAs, ENST00000608936 and ENST00000433747, show promise as diagnostic markers for AD, with ML models achieving > 95% sensitivity, specificity, and accuracy in both the training and testing datasets. These findings suggest that the expression profiles of lncRNAs could significantly contribute to advancing personalized AD diagnosis in this community, offering promising avenues for early detection and follow-up.

A distance-based kernel for classification via Support Vector Machines.

Support Vector Machines (SVMs) are a type of supervised machine learning algorithm widely used for classification tasks. In contrast to traditional methods that split the data into separate training and testing sets, here we propose an innovative approach where subsets of the original data are randomly selected to train the model multiple times. This iterative training process aims to identify a representative data subset, leading to improved inferences about the population. Additionally, we introduce a novel distance-based kernel specifically designed for binary-type features based on a similarity matrix that efficiently handles both binary and multi-class classification problems. Computational experiments on publicly available datasets of varying sizes demonstrate that our proposed method significantly outperforms existing approaches in terms of classification accuracy. Furthermore, the distance-based kernel achieves superior performance compared to other well-known kernels from the literature and those used in previous studies on the same datasets. These findings validate the effectiveness of our proposed classification method and distance-based kernel for SVMs. By leveraging random subset selection and a unique kernel design, we achieve notable improvements in classification accuracy. These results have significant implications for diverse classification problems in Machine Learning and data analysis.

Optic nerve haemangioblastoma in association with von Hippel-Lindau syndrome: case report and literature review.

Optic nerve haemangioblastoma (ONH) is an uncommon, benign, non-meningothelial, mesenchymal tumour of unclear origin. Most are associated with von Hippel-Lindau (VHL) syndrome (71%), and only 40 cases have been reported in the medical literature. Most of the patients develop non-specific visual symptoms, including decreased visual acuity and/or loss of visual fields, exophthalmos, trigeminal neuralgia, and retroorbital pain. Optic nerve sheath meningioma and optic nerve glioma are among the differential diagnoses that may be considered in this location. Contrast-enhanced MRI is considered an optimal diagnostic tool, which helps to determine some characteristics that guide towards an adequate diagnosis and treatment. We present a 42-year-old patient with a history of VHL syndrome in whom a cerebellar lesion and optic nerve lesions were evidenced, and we did a review of the literature and case analysis.

Theory of Mind in Huntington's Disease: A Systematic Review of 20 Years of Research.

Background: People with Huntington's disease (HD) exhibit neurocognitive alterations throughout the disease, including deficits in social cognitive processes such as Theory of Mind (ToM). Objective: The aim is to identify methodologies and ToM instruments employed in HD, alongside relevant findings, within the scientific literature of the past two decades. Methods: We conducted a comprehensive search for relevant papers in the SCOPUS, PubMed, APA-PsyArticles, Web of Science, Redalyc, and SciELO databases. In the selection process, we specifically focused on studies that included individuals with a confirmed genetic status of HD and investigated ToM functioning in patients with and without motor symptoms. The systematic review followed the PRISMA protocol. Results: A total of 27 papers were selected for this systematic review, covering the period from 2003 to 2023. The findings consistently indicate that ToM is globally affected in patients with manifest motor symptoms. In individuals without motor symptoms, impairments are focused on the affective dimensions of ToM. Conclusions: Based on our analysis, affective ToM could be considered a potential biomarker for HD. Therefore, it is recommended that ToM assessment be included as part of neuropsychological evaluation protocols in clinical settings. Suchinclusion could aid in the identification of early stages of the disease and provide new opportunities for treatment, particularly with emerging drugs like antisense oligomers. The Prospero registration number for this review is CRD42020209769.

Genetic modifiers of cognitive decline in PSEN1 E280A Alzheimer's disease.

INTRODUCTION: Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic variants in AD. METHODS: RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole-exome sequencing for association with common exonic functional variants. Findings were validated in post mortem brain tissue. RESULTS: One hundred seventy-two gene variants in FAD, and 227 gene variants in SAD associated with RCD. In FAD, performance decline of the immediate recall of the Rey-Osterrieth figure test associated with 122 genetic variants. Olfactory receptor OR51B6 showed the highest number of associated variants. Its expression was detected in temporal cortex neurons. DISCUSSION: Impaired olfactory function has been associated with cognitive impairment in AD. Genetic variants in these or other genes could help to identify risk of faster memory decline in FAD and SAD patients.

Assessment of risk-adjusted mortality ratio (RAMR) in bloodstream infections using all-patient refined diagnosis-related groups (APR-DRGs).

OBJECTIVES: To calculate a risk-adjusted mortality ratio (RAMR) for bloodstream infections (BSIs) using all-patient refined diagnosis-related groups (APR-DRGs) and compare it with the crude mortality rate (CMR). METHODS: Retrospective observational study of prevalent BSI at our institution from January 2019 to December 2022. In-hospital mortality was adjusted with a binary logistic regression model adjusting for sex, age, admission type and mortality risk for the hospitalization episode according to the four severity levels of APR DRGs. The RAMR was calculated as the ratio of observed to expected in-hospital mortality, and the CMR was calculated as the proportion of deaths among all bacteraemia episodes. RESULTS: Of 2939 BSIs, 2541 were included: Escherichia coli (n = 1310), Klebsiella pneumoniae (n = 428), Pseudomonas aeruginosa (n = 209), Staphylococcus aureus (n = 498) and candidaemia (n = 96). A total of 436 (17.2%) patients died during hospitalization and 279 died within the first 14 days after the onset of BSI. Throughout the period, all BSI cases had a mortality rate above the expected adjusted mortality (RAMR value greater than 1), except for Escherichia coli (1.03; 95% CI 0.86-1.21). The highest overall RAMR values were observed for P. aeruginosa, Candida and S. aureus with 2.06 (95% CI 1.57-2.62), 1.99 (95% CI 1.3-2.81) and 1.8 (95% CI 1.47-2.16), respectively. The temporal evolution of CMR may differ from RAMR, especially in E. coli, where it was reversed. CONCLUSIONS: RAMR showed higher than expected mortality for all BSIs studied except E. coli and provides complementary to and more clinically comprehensive information than CMR, the currently recommended antibiotic stewardship programme mortality indicator.

Sex differences in population versus in-hospital use of aortic valve replacement procedures in Spain.

BACKGROUND AND AIMS: It is not well known if sex differences in the use and results of aortic valve replacement (AVR) are changing. The aim of the study is to assess the time trends in the differences by sex in the utilisation of AVR procedures in hospitals and in the community. METHODS: Retrospective observational analysis using data from the Spanish National Hospitalizations Administrative Database. All hospitalisations between 2016 and 2021 with a main diagnosis of aortic stenosis (ICD-10 codes: I35.0 and I35.2) were included. Time trends in hospitalisation, AVRs and hospital outcomes were analysed. Crude utilisation and population-standardised rates were calculated. RESULTS: During the study period, 64 384 hospitalisations in 55 983 patients (55.5% men) with 36 915 (65,9%) AVR were recorded. Of these, 15 563 (42.2%) were transcatheter and 21 432 (58.0%) surgical. At hospital level, transcatheter procedures were more frequently performed in women (32.3% vs 24.2%, p < 0.001) and surgical in men (42.9% vs. 32.5%, p < 0.001) but at the population level, surgical and transcatheter aortic valve replacements were used more frequently in men (12.6 surgical and 8.0 transcatheter per 100 000 population) vs women (6.4 and 5.8, respectively; p < 0.001 for both comparisons). Transcatheter procedures shifted from 17.3% in 2016 to 38.0% in 2021, overtaking surgical procedures in 2018 for women and 2021 for men. CONCLUSIONS: TAVR has displaced SAVR as the most frequent AVR procedure in Spain by 2020. This occurred earlier in women, who despite the greater weight of their age group in the older population, receive fewer AVRs, both SAVR and TAVR.

Masa nasal como único compromiso extrapulmonar de infección por M. Tuberculosis / Nasal mass as the only extrapulmonary compromise of M. Tuberculosis infection / Massa nasal como único compromisso extrapulmonar da infecção por M. Tuberculose

La tuberculosis aún es un problema de salud pública mundial. La infección causada por Mycobacterium tuberculosis se manifiesta de forma principal a nivel pulmonar. Sin embargo, alrededor del 20 % de los casos se presentan en otras localizaciones anatómicas y solo el 2 % tiene afectación del tracto respiratorio superior. Se presenta el caso de una mujer de 75 años, reconsultante al servicio de otorrinolaringología por epistaxis, lesiones postillosas en cavidad nasal y hallazgo de masa nasal. Posterior a la resección quirúrgica de la lesión, se logró la comprobación microbiológica de infección por M. tuberculosis. Se realizan estudios para descartar compromiso pulmonar y de otras localizaciones. Posterior al inicio de tratamiento antituberculoso se logró resolución completa de la lesión y no recurrencia de los síntomas. Las formas extrapulmonares de la infección por M. tuberculosis y, en especial las que afectan la región de la cabeza y el cuello, requieren un alto índice de sospecha para su diagnóstico. Los métodos de diagnóstico como la prueba de PCR y los cultivos de tejidos permiten un óptimo inicio del manejo médico de acuerdo con la epidemiología local y las condiciones del paciente.

Tuberculosis is still a global public health burden. Infection caused by the bacillus Mycobacterium tuberculosis (M. Tuberculosis) manifests mainly in the lungs. However, around 20 % of cases occur in other anatomical locations and only 2 % have upper respiratory tract involvement. We present the case of a 75-year-old female patient, who returned to the otorhinolaryngology service due to epistaxis and postillomous lesions in the nasal cavity with a finding of a nasal mass. After surgical resection of the lesion, microbiological confirmation of M. tuberculosis infection is achieved. Studies are performed to rule-out lung involvement, as well as other locations. After the initiation of tuberculosis treatment, complete resolution of the lesion and no recurrence of symptoms is documented. Extrapulmonary forms of M. tuberculosis infection, and especially those involving the head and neck region, require a high index of suspicion for their diagnosis. Diagnostic methods such as PCR testing and tissue cultures allow optimal initiation of medical management according to local epidemiology and patient conditions.

A tuberculose ainda é um problema de saúde pública global. A infecção causada pelo Mycobacterium tuberculoses manifesta-se principalmente nos pulmões. Entretanto, cerca de 20% dos casos ocorrem em outras localizações anatômicas e apenas 2% apresentam comprometimento do trato respiratório superior. É apresentado o caso de uma mulher de 75 anos que retornou ao serviço de otorrinolaringologia por quadro de epistaxe, lesões com crostas em cavidade nasal e descoberta de massa nasal. Após ressecção cirúrgica da lesão, foi realizada verificação microbiológica de infecção por M. tuberculoses. Estudos são realizados para descartar envolvimento pulmonar e otras localizações. Após início do tratamento antituberculoso, houve resolução completa dalesão e não houve recidiva dos sintomas. As formas extrapulmonares da infecção por M. tuberculoses, especialmente aquelas que acometem a região de cabeça e pescoço, requerem alto índice de suspeita para diagnóstico. Métodos de diagnóstico, como testes de PCR e culturas de tecidos, permitem o início ideal do tratamento médico de acordó com a epidemiologia local e as condições do paciente.

Uncovering the Genetic and Molecular Features of Huntington's Disease in Northern Colombia.

Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.

Leading consumption patterns of psychoactive substances in Colombia: A deep neural network-based clustering-oriented embedding approach.

The number of health-related incidents caused using illegal and legal psychoactive substances (PAS) has dramatically increased over two decades worldwide. In Colombia, the use of illicit substances has increased up to 10.3%, while the consumption alcohol and tobacco has increased to 84% and 12%, respectively. It is well-known that identifying drug consumption patterns in the general population is essential in reducing overall drug consumption. However, existing approaches do not incorporate Machine Learning and/or Deep Data Mining methods in combination with spatial techniques. To enhance our understanding of mental health issues related to PAS and assist in the development of national policies, here we present a novel Deep Neural Network-based Clustering-oriented Embedding Algorithm that incorporates an autoencoder and spatial techniques. The primary goal of our model is to identify general and spatial patterns of drug consumption and abuse, while also extracting relevant features from the input data and identifying clusters during the learning process. As a test case, we used the largest publicly available database of legal and illegal PAS consumption comprising 49,600 Colombian households. We estimated and geographically represented the prevalence of consumption and/or abuse of both PAS and non-PAS, while achieving statistically significant goodness-of-fit values. Our results indicate that region, sex, housing type, socioeconomic status, age, and variables related to household finances contribute to explaining the patterns of consumption and/or abuse of PAS. Additionally, we identified three distinct patterns of PAS consumption and/or abuse. At the spatial level, these patterns indicate concentrations of drug consumption in specific regions of the country, which are closely related to specific geographic locations and the prevailing social and environmental contexts. These findings can provide valuable insights to facilitate decision-making and develop national policies targeting specific groups given their cultural, geographic, and social conditions.

Differences in clinical outcomes, health care resource utilization and costs in heart failure patients according to left ventricular ejection fraction.

INTRODUCTION AND OBJECTIVES: The impact of left ventricular ejection fraction (LVEF) on health care resource utilization (HCRU) and cost in heart failure (HF) patients is not well known. We aimed to compare outcomes, HCRUs and costs according to LVEF groups. METHODS: Retrospective, observational study of all patients with an emergency department (ED) visit or admission to a tertiary hospital in Spain 2018 with a primary HF diagnosis. We excluded patients with newly diagnosed heart failure. One-year clinical outcomes, costs and HCRUs were compared according to LVEF (reduced [HFrEF], mildly reduced [HFmrEF], and preserved [HFpEF]). RESULTS: Among 1287 patients with a primary diagnosis of HF in the ED, 365 (28.4%) were discharged to home (ED group), and 919 (71.4%) were hospitalized (hospital group [HG]). In total, 190 patients (14.7%) had HFrEF, 146 (11.4%) HFmrEF, and 951 (73.9%) HFpEF. The mean age was 80.1±10.7 years; 57.1% were female. The median [interquartile range] of costs per patient/y was €1889 [259-6269] in the ED group and €5008 [2747-9589] in the HG (P <.001). Hospitalization rates were higher in patients with HFrEF in the ED group. The median costs of HFrEF per patient/y were higher in patients in both groups: €4763 [2076-17 155] vs €3900 [590-8013] for HFmrEF vs €3812 [259-5486] for HFpEF in the ED group, and €6321 [3335-796] vs €6170 [3189-10484] vs €4636 [2609-8977], respectively, in the hospital group (all P <.001). This difference was driven by the more frequent admission to intensive care units, and greater use of diagnostic and therapeutic tests among HFrEF patients. CONCLUSIONS: In HF, LVEF significantly impacts costs and HCRU. Costs were higher in patients with HFrEF, especially those requiring hospitalization, than in those with HFpEF.

Ancestry component as a major predictor of lithium response in the treatment of bipolar disorder.

BACKGROUND: Bipolar Disorder (BD) represents the seventh major cause of disability life-years-adjusted. Lithium remains as a first-line treatment, but clinical improvement occurs only in 30 % of treated patients. Studies suggest that genetics plays a major role in shaping the individual response of BD patients to lithium. METHODS: We used machine-learning techniques (Advance Recursive Partitioned Analysis, ARPA) to build a personalized prediction framework of BD lithium response using biological, clinical, and demographical data. Using the Alda scale, we classified 172 BD I-II patients as responders or non-responders to lithium treatment. ARPA methods were used to build individual prediction frameworks and to define variable importance. Two predictive models were evaluated: 1) demographic and clinical data, and 2) demographic, clinical and ancestry data. Model performance was assessed using Receiver Operating Characteristic (ROC) curves. RESULTS: The predictive model including ancestry yield the best performance (sensibility = 84.6 %, specificity = 93.8 % and AUC = 89.2 %) compared to the model without ancestry (sensibility = 50 %, Specificity = 94.5 %, and AUC = 72.2 %). This ancestry component best predicted lithium individual response. Clinical variables such as disease duration, the number of depressive episodes, the total number of affective episodes, and the number of manic episodes were also important predictors. CONCLUSION: Ancestry component is a major predictor and significantly improves the definition of individual Lithium response in BD patients. We provide classification trees with potential bench application in the clinical setting. While this prediction framework might be applied in specific populations, the used methodology might be of general use in precision and translational medicine.

Nitrate removal and environmental side-effects controlled by hydraulic residence time in woodchip bioreactors treating cold agricultural drainage water.

Denitrifying woodchip bioreactors (WBRs) remove nitrate (NO3-) from agricultural drainage water at field-scale, but their efficacy at cold temperatures remains uncertain. This study shows how hydraulic residence time (HRT) controls NO3- removal and environmental side-effects of WBRs at low water temperature under pilot-scale conditions with controlled operation of nine WBRs (94 dm3). Hydraulic properties were assessed by a bromide tracer test, and NO3- removal, emissions of nitrous oxide (N2O) and methane (CH4), and losses of dissolved organic carbon (DOC) were measured at HRTs of 5-30 h. Inlet NO3- concentrations were increasingly reduced at higher HRTs. The relationship between HRT and the efficiency (%) of NO3- removal was linear (Radj2 = 0.94), while the relationship between HRT and NO3- reduction rates (NRR) was logistic (Radj2 = 0.88). Gaseous emissions of N2O were equally low at HRTs of 10-30 h, but higher at 5 h (P < 0.05). Methane fluxes were small, but with consistent emissions at HRTs of 20-30 h and uptake at 5-15 h. HRT had limited effect on effluent DOC concentrations, but strong effect on mass losses that were five-fold higher (320 mg L-1) at the HRT of 5 h than at 30 h. In summary, at cold temperatures HRTs of ≤ 20 h resulted in suboptimal NRR, accelerating DOC losses, and increased risk of N2O losses at least below a threshold HRT of 5-10 h. HRTs of 20-30 h gave maximal NRR, smallest losses of DOC and N2O, but an increased risk of CH4 emissions.

E-Learning versus Face-to-Face Methodology for Learning Antimicrobial Resistance and Prescription Practice in a Tertiary Hospital of a Middle-Income Country.

Background: Antimicrobial resistance is a growing health problem worldwide. One strategy to face this problem in a reasonable way is training health personnel for the rational use of antimicrobials. There are some difficulties associated with medical staff to receiving training with E-learning education, but there is a lack of studies and insufficient evidence of the effectiveness of this method compared to face-to-face learning. Methods: An educational intervention on antimicrobial resistance (AMR) and antimicrobial prescription practice (APP) was designed and implemented using two approaches: face-to-face and E-learning among physicians of the intensive care unit (ICU) and internal medicine ward (IMW) at Eugenio Espejo Hospital in Quito. Modalities of interventions were compared to propose a strategy of continuous professional development (CPD) for all hospital staff. An interventional study was proposed using a quasi-experimental approach that included 91 physicians, of which 49 belong to the IMW and 42 to the ICU. All of them received training on AMR­half in a face-to-face mode and the other half in an asynchronous E-learning mode. They then all participated on APP training but with switched groups; those who previously participated in the face-to-face experience participated in an E-learning module and vice-versa. We evaluated self-perception about basic knowledge, attitudes and referred practices towards AMR and APP before and after the intervention. A review of medical records was conducted before and after training by checking antimicrobial prescriptions for all patients in the ICU and IMW with bacteremia, urinary tract infection (UTI), pneumonia, and skin and soft tissue infection. The study received IRB clearance, and we used SPSS for statistical analysis. Results: No statistically significant difference was observed between the E-learning and the face-to-face methodology for AMR and APP. Both methodologies improved knowledge, attitudes and referred practices. In the case of E-learning, there was a self-perception of improved attitudes (p < 0.05) and practices (p < 0.001) for both AMR and APP. In face-to-face, there was a perception of improvement only in attitudes (p < 0.001) for APP. In clinical practice, the use of antimicrobials significantly improved in all domains after training, including empirical and targeted treatment of bacteremia and pneumonia (p < 0.001) and targeted treatment of UTI (p < 0.05). For the empirical treatment of pneumonia, the mean number of antibiotics was reduced from 1.87 before to 1.05 after the intervention (p = 0.003), whereas in the targeted management of bacteremia, the number of antibiotics was reduced from 2.19 to 1.53 (p = 0.010). Conclusions: There was no statistically significant difference between the effect of E-learning and face-to-face strategy in terms of teaching AMR and APP. Adequate self-reported attitudes and practices in E-learning exceed those of the face-to-face approach. The empiric and targeted use of antimicrobials improved in all reviewed cases, and we observed an overall decrease in antibiotic use. Satisfaction with training was high for both methods, and participants valued the flexibility and accessibility of E-learning.

ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP.

Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD.

Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics-Molecular Mechanics Framework.

A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.