Investigation of the hospital pharmacy profession in Europe.

OBJECTIVE: From 1995, the European Association of Hospital Pharmacists (EAHP) has regularly investigated the progress of the hospital pharmacy profession in Europe, and identified key barriers and drivers of this. The most recent 'Investigation of the Hospital Pharmacy Profession in Europe' was conducted from November 2022 to March 2023. METHODS: The online questionnaire was sent to all hospital pharmacies in EAHP member countries. The investigation was drafted using the same questions as the 2015 baseline survey. Where possible and relevant, responses were compared with the data from previous surveys that monitored the implementation of the EAHP statements. Keele University, Centre for Medicines Optimisation, School of Pharmacy and Bioengineering, UK analysed the data. RESULTS: The overall number of responses was 653, with a better response rate of 19% compared with 14% in 2018 statements survey. The findings indicated that participating hospital pharmacies have similar characteristics to previous surveys. Section 1 (Introductory statements and governance), section 2 (Selection, procurement and distribution), section 3 (Production and compounding), section 5 (Patient safety and quality assurance) questions were generally answered positively, with results ranging from 52% to 90%. However, results for section 4 (Clinical pharmacy services) returned lower levels of positivity, with responses from 8 of the 15 questions being less than 60%. When asked what is preventing hospital pharmacists from achieving implementation of these activities, most answers were limited capacity, not considered to be a priority by managers, or other healthcare professionals do this. The last section focused on self-assessment and action planning, with fewer than 50% of positive responses; COVID-19 preparedness and vaccines with mixed positive and negative responses. Furthermore, implementation of the falsified medicines directive impacted the medication handling processes in 50% or more of the answers. Regarding sustainability, the majority (59%) of respondents felt a greater focus should be on sustainability from an organisational or management perspective. CONCLUSION: Results offer valuable insights into the hospital pharmacy profession throughout Europe. While there have been improvements in certain areas, challenges remain, particularly in implementing clinical pharmacy services. The findings provide a foundation for further dialogue, advocacy, and strategic planning to advance the role of hospital pharmacists and enhance patient care in Europe's healthcare systems.

[Inequalities in time to diagnosis of Down Syndrome in Bolivia]. / Desigualdades en el tiempo hasta el diagnóstico del síndrome de Down en Bolivia.

Down Syndrome is the most common genetic condition and a leading cause of intellectual disability. Individuals in rural areas, particularly those with disabilities, often face disparities in healthcare access. Analyzing clinical records of patients diagnosed with Down Syndrome between 2013 and 2022 by the Institute of Genetics at the Universidad Mayor de San Andrés in La Paz, Bolivia, this study examined the time to diagnosis for 250 patients with Down Syndrome. The findings revealed that patients from rural areas with Down Syndrome take an average of five months to receive a diagnosis, compared to two months in urban areas (p<0.001). No significant differences were found in the time to diagnosis based on gender. However, a higher proportion of males from rural areas was observed (p=0.03). The results suggest that individuals in rural areas face challenges in receiving a timely diagnosis. On the other hand, women may not be brought to cities for proper diagnosis and treatment due to gender biases in certain communities. The importance of improving access to early diagnosis and treatment in rural areas is emphasized.

El síndrome de Down es la condición genética más común y una causa principal de discapacidad intelectual. Las personas en áreas rurales, especialmente aquellas con discapacidades, a menudo enfrentan desigualdades en el acceso a la salud. A partir de los registros clínicos de pacientes con diagnóstico confirmado de síndrome de Down entre 2013 y 2022, por el Instituto de Genética de la Universidad Mayor de San Andrés, La Paz, Bolivia, se analizó, analizó el tiempo hasta el diagnóstico de 250 pacientes con síndrome de Down, mostró que los pacientes procedentes de áreas rurales con síndrome de Down tardan cinco meses en promedio en recibir un diagnóstico, comparado a los dos meses en zonas urbanas (p<0,001). No se encontraron diferencias significativas en el tiempo hasta el diagnostico según el sexo. Sin embargo, se evidenció una mayor proporción de varones provenientes de áreas rurales (p=0,03). Los hallazgos sugieren que los individuos de áreas rurales enfrentan dificultades para recibir el diagnóstico. Por otro lado, las mujeres quizás no sean llevadas a ciudades para un diagnóstico y tratamiento adecuado debido a sesgos de género en ciertas comunidades. Se subraya la importancia de mejorar el acceso a diagnósticos y tratamientos tempranos en áreas rurales.

Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

Activating Transcription Factor 5 Promotes Neuroblastoma Metastasis by Inducing Anoikis Resistance.

MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. SIGNIFICANCE: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.

Novel Kinetic Resolution of Thiazolo-Benzimidazolines Using MAO Enzymes.

The kinetic resolution of racemic 1H,3H-thiazolo[3,4-a]benzimidazoline (TBIM) heterocycles was achieved using E. coli whole cells expressing the MAO-N D11 enzyme. Several cosolvents were screened using TBIM 2a as the substrate. DMF was the best cosolvent, affording the pure enantiomer (+)-2a in 44% yield, 94% ee. The stereochemistry of TBIM was predicted by means of ab initio calculations of optical rotation and circular dichroism spectra. The reaction scope was investigated for 11 substituted (±) TBIM using an optimized protocol. The best yield and % ee were obtained for the nonsubstituted 2a. Among the substituted compounds, the 5-substituted-TBIM showed better % ee than the 4-substituted one. The small electron donor group (Me) led to better % ee than the electron-withdrawing groups (-NO2 and -CO2Et), and the bulky naphthyl group was detrimental for the kinetic resolution. Docking experiments and molecular dynamics (MD) simulations were employed to further understand the interactions between MAO-N D11 and the thiazolo-benzimidazoline substrates. For 2a, the MD showed favorable positioning and binding energy for both enantiomers, thus suggesting that this kinetic resolution is influenced not only by the active site but also by the entry tunnel. This work constitutes the first report of the enzymatic kinetic resolution applied to TBIM heterocycles.

Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors.

Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extracranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multidimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell type-specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies. SIGNIFICANCE: Comprehensive characterization of lncRNAs in pediatric cancer leads to the identification of highly expressed lncRNAs across childhood cancers, annotation of lncRNAs showing histotype-specific elevated expression, and prediction of lncRNA gene regulatory networks.

PanDrugs2: prioritizing cancer therapies using integrated individual multi-omics data.

Genomics studies routinely confront researchers with long lists of tumor alterations detected in patients. Such lists are difficult to interpret since only a minority of the alterations are relevant biomarkers for diagnosis and for designing therapeutic strategies. PanDrugs is a methodology that facilitates the interpretation of tumor molecular alterations and guides the selection of personalized treatments. To do so, PanDrugs scores gene actionability and drug feasibility to provide a prioritized evidence-based list of drugs. Here, we introduce PanDrugs2, a major upgrade of PanDrugs that, in addition to somatic variant analysis, supports a new integrated multi-omics analysis which simultaneously combines somatic and germline variants, copy number variation and gene expression data. Moreover, PanDrugs2 now considers cancer genetic dependencies to extend tumor vulnerabilities providing therapeutic options for untargetable genes. Importantly, a novel intuitive report to support clinical decision-making is generated. PanDrugs database has been updated, integrating 23 primary sources that support >74K drug-gene associations obtained from 4642 genes and 14 659 unique compounds. The database has also been reimplemented to allow semi-automatic updates to facilitate maintenance and release of future versions. PanDrugs2 does not require login and is freely available at https://www.pandrugs.org/.

Examining the association between exposome score for schizophrenia and cognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

BACKGROUND: People with schizophrenia spectrum disorders (SSD) frequently present cognitive impairments. Here, we investigated whether the exposome score for schizophrenia (ES-SCZ) - a cumulative environmental exposure score - was associated with impairments of neurocognition, social cognition, and perception in patients with SSD, their unaffected siblings, and healthy controls. METHODS: This cross-sectional sample consisted of 1200 patients, 1371 siblings, and 1564 healthy controls. Neurocognition, social cognition, and perception were assesed using a short version of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Degraded Facial Affect Recognition Task (DFAR), and the Benton Facial Recognition Test (BFR), respectively. Regression models were used to analyze the association between ES-SCZ and cognitive domains in each group. RESULTS: There were no statistically significant associations between ES-SCZ and cognitive domains in SSD. ES-SCZ was negatively associated with T-score of cognition in siblings (B=-0.40, 95% CI -0.76 to -0.03) and healthy controls (B=-0.63, 95% CI -1.06 to -0.21). Additionally, ES-SCZ was positively associated with DFAR-total in siblings (B=0.83, 95% CI 0.26 to 1.40). Sensitivity analyses excluding cannabis use history from ES-SCZ largely confirmed the main findings. CONCLUSIONS: Longitudinal cohorts may elucidate how environmental exposures influence the onset and course of cognitive impairments in trans-syndromic psychosis spectrum.

Germline pathogenic variants in 786 neuroblastoma patients.

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear. Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients. Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival. Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival. Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01). Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.

Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers.

Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

The Rhizopus Holobiont: A Model to Decipher Fungal-Bacterial-Viral Symbioses.

Rhizopus microsporus is an early-diverging fungal species that inhabits the soil, is used for the fermentation of diverse Asian and African foods, and can be a pathogen of plants, animals, and humans.Toxin-producing strains of R. microsporus live in symbiosis with Gram-negative betaproteobacteria from the genus Mycetohabitans (Burkholderia sensu lato). These bacterial endosymbionts increase the metabolic plasticity of the fungal holobiont by producing the "mycotoxins," control their asexual reproduction, and influence their sexual success. Recently, we identified two viruses of the genus Narnavirus in some R. microsporus strains that harbor Mycetohabitans. By eliminating bacteria and/or viruses from host R. microsporus strains, we have been able to study the role of these symbionts in fungal biology. Remarkably, the absence of these bacterial and viral symbionts decreases sexual reproduction. In this chapter, the method developed to eliminate and genotype the Narnavirus RmNV-20S and RmNV-23S in R. microsporus is described in detail.

Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants.

BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. RESULTS: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

A reinforcement learning approach to improve the performance of the Avellaneda-Stoikov market-making algorithm.

Market making is a high-frequency trading problem for which solutions based on reinforcement learning (RL) are being explored increasingly. This paper presents an approach to market making using deep reinforcement learning, with the novelty that, rather than to set the bid and ask prices directly, the neural network output is used to tweak the risk aversion parameter and the output of the Avellaneda-Stoikov procedure to obtain bid and ask prices that minimise inventory risk. Two further contributions are, first, that the initial parameters for the Avellaneda-Stoikov equations are optimised with a genetic algorithm, which parameters are also used to create a baseline Avellaneda-Stoikov agent (Gen-AS); and second, that state-defining features forming the RL agent's neural network input are selected based on their relative importance by means of a random forest. Two variants of the deep RL model (Alpha-AS-1 and Alpha-AS-2) were backtested on real data (L2 tick data from 30 days of bitcoin-dollar pair trading) alongside the Gen-AS model and two other baselines. The performance of the five models was recorded through four indicators (the Sharpe, Sortino and P&L-to-MAP ratios, and the maximum drawdown). Gen-AS outperformed the two other baseline models on all indicators, and in turn the two Alpha-AS models substantially outperformed Gen-AS on Sharpe, Sortino and P&L-to-MAP. Localised excessive risk-taking by the Alpha-AS models, as reflected in a few heavy dropdowns, is a source of concern for which possible solutions are discussed.

Preclinical efficacy of the Wnt/ß-catenin pathway inhibitor BC2059 for the treatment of desmoid tumors.

Mutation in the CTNNB1 gene, leading to a deregulation of the WTN/ß-catenin pathway, is a common feature of desmoid tumors (DTs). Many ß-catenin inhibitors have recently been tested in clinical studies; however, BC2059 (also referred as Tegavivint), a selective inhibitor of nuclear ß-catenin that works through binding TBL-1, is the only one being evaluated in a clinical study, specifically for treatment of desmoid tumor patients. Preclinical studies on BC2059 have shown activity in multiple myeloma, acute myeloid leukemia and osteosarcoma. Our preclinical studies provide data on the efficacy of BC2059 in desmoid cell lines, which could help provide insight regarding antitumor activity of this therapy in desmoid tumor patients. In vitro activity of BC2059 was evaluated using desmoid tumor cell lines. Ex vivo activity of BC2059 was assessed using an explant tissue culture model. Pharmacological inhibition of the nuclear ß-catenin activity using BC2059 markedly inhibited cell viability, migration and invasion of mutated DT cells, but with lower effect on wild-type DTs. The decrease in cell viability of mutated DT cells caused by BC2059 was due to apoptosis. Treatment with BC2059 led to a reduction of ß-catenin-associated TBL1 in all mutated DT cells, resulting in a reduction of nuclear ß-catenin. mRNA and protein levels of AXIN2, a ß-catenin target gene, were also found to be downregulated after BC2059 treatment. Taken together, our results demonstrate that nuclear ß-catenin inhibition using BC2059 may be a novel therapeutic strategy for desmoid tumor treatment, especially in patients with CTNNB1 mutation.

Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease. METHODS: In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home. RNA from the fingerstick blood was tested using DxTerity's 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method. RESULTS: Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease. From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to patients with mild to moderate disease conditions. These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases. These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA). Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives). CONCLUSIONS: Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity. These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits.

Addition of clinoptilolite in the diet reduces uterine PMN leukocytes and open days in multiparous lactating dairy cows managed in a mountain tropical pasture-based system.

This study aimed to assess the effect of adding clinoptilolite in the diet on uterine health and reproductive performance in multiparous lactating dairy cows managed in a tropical pasture-based system above 2500 m of altitude. Seventy-seven multiparous Holstein crossbred cows from two farms were allocated randomly into two groups: clinoptilolite supplemented cows (CLG, n = 42) and non-supplemented cows as control (CG, n = 35). Cows from CLG were supplemented with clinoptilolite from 30 days (50 g/cow/day) before to 60 days after calving (200 g/cow/day). In CLG cows, percentages of uterine PMN leukocytes (P < 0.0001) and proportion of subclinical endometritis (P = 0.0187) were lower than in CG. The interval calving to first corpus luteum was shorter (P = 0.0759) in CLG than CG, and calving to first service interval was similar between treatments. Cows from CLG became pregnant 35 days earlier than CG cows (P = 0.0224). On farm A, calving to conception interval was 18.1 days longer in CLG than in CG (P = 0.3750); in farm B, this interval was 86.2 days shorter in CLG than in CG (P = 0.0002). In conclusion, daily addition of clinoptilolite in the diet decreased the percentage of uterine PMN leukocytes, the proportion of cows with subclinical endometritis, and shortened the calving-conception interval in multiparous lactating dairy cows.

Determination of the Physiological Age in Two Tephritid Fruit Fly Species Using Artificial Intelligence.

The Mexican fruit fly (Anastrepha ludens, Loew, Diptera: Tephritidae) and the Mediterranean fruit fly (Ceratitis capitata, Wiedemann, Diptera: Tephritidae) are among the world's most damaging pests affecting fruits and vegetables. The Sterile Insect Technique (SIT), which consists in the mass-production, irradiation, and release of insects in affected areas is currently used for their control. The appropriate time for irradiation, one to two days before adult emergence, is determined through the color of the eyes, which varies according to the physiological age of pupae. Age is checked visually, which is subjective and depends on the technician's skill. Here, image processing and Machine Learning techniques were implemented as a method to determine pupal development using eye color. First, Multi Template Matching (MTM) was used to correctly crop the eye section of pupae for 96.2% of images from A. ludens and 97.5% of images for C. capitata. Then, supervised Machine Learning algorithms were applied to the cropped images to classify the physiological age according to the color of the eyes. Algorithms based on Inception v1, correctly identified the physiological age of maturity at 2 d before emergence, with a 75.0% accuracy for A. ludens and 83.16% for C. capitata, respectively. Supervised Machine Learning algorithms based on Neural Networks could be used as support in determining the physiological age of pupae from images, thus reducing human error and uncertainty in decisions as when to irradiate. The development of a user interface and an automatization process could be further developed, based on the data obtained on this study.

The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Schizophrenia is frequently accompanied with social cognitive disturbances. Cannabis represents one established environmental factor associated with the onset and progression of schizophrenia. The present cross-sectional study aimed to investigate the association of facial emotion recognition (FER) performance with cannabis use in 2039 patients with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). FER performance was measured using the Degraded Facial Affect Recognition Task (DFAR). Better FER performance as indicated by higher DFAR-total scores was associated with lifetime regular cannabis use in schizophrenia (B = 1.36, 95% CI 0.02 to 2.69), siblings (B = 2.17, 95% CI 0.79 to 3.56), and HC (B = 3.10, 95% CI 1.14 to 5.06). No associations were found between DFAR-total and current cannabis use. Patients with schizophrenia who started to use cannabis after the age of 16 showed better FER performance than patients who started earlier (B = 2.50, 95% CI 0.15 to 4.84) and non-users (B = 3.72, 95 CI 1.96 to 5.49). Better FER performance was found also in siblings who started to use cannabis after 16 compared to non-users (B = 2.37, 95% CI 0.58 to 4.16), while HC using cannabis performed better than non-users at DFAR-total regardless of the age at onset. Our findings suggest that lifetime regular cannabis use may be associated with better FER regardless of the psychosis risk, but that FER might be moderated by age at first use in people with higher genetic risk. Longitudinal studies may clarify whether there is a cause-and-effect relationship between cannabis use and FER performance in psychotic and non-psychotic samples.