Retrospective analysis of 302 ovine dystocia cases presented to a veterinary hospital with particular attention to uterine torsion

Background Dystocia is common in sheep, and foetal causes are predominant. Among maternal causes, insufficient cervical dilatation is the most frequent problem. Uterine torsion has been considered rare by many authors. Objectives This study was conducted to investigate causes of dystocia in sheep presented for veterinary attention, and particular focus was set on the description of uterine torsion and analysis of potentially predisposing factors for this condition. Methods Clinical records of 302 sheep treated for dystocia were evaluated retrospectively. Known and proposed risk factors for uterine torsion in cattle were analysed regarding their potential importance in sheep. These included lamb birth weights, ewe age, parity, season, nutrition, breed type, litter size and husbandry. Results Maternal causes of dystocia accounted for 67.2% (203/302) of the presented cases. Of these, insufficient cervical dilatation (121/203, 59.6%) was the most frequent diagnosis. Another substantial proportion of maternal causes (60/203, 29.6%) was identified as uterine torsion. Husbandry, breed type and litter size showed significance in univariate analyses, with lower odds for meat breeds (OR 0.22; p < 0.001), twin- (OR 0.49; p = 0.020) or multiple-bearing ewes (OR 0.19; p = 0.013) and higher odds for fully housed animals (OR 17.87; p < 0.001). Year-round housing was identified as the most influential factor in a subsequent multivariate analysis. Conclusions Uterine torsion was identified as a relevant cause of dystocia in our case load. The condition is likely to be underdiagnosed in sheep, and increased farmer and veterinary awareness is necessary to ensure adequate treatment of affected animals and to prevent unnecessary suffering

Meta-analysis of genes in commercially available nutrigenomic tests denotes lack of association with dietary intake and nutrient-related pathologies

Nutrigenomics is an emerging discipline that aims to investigate how individual genetic composition correlates with dietary intake, as well as how nutrition influences gene expression. Herein, the fundamental question relates to the value of nutrigenomics testing on the basis of the currently available scientific evidence. A thorough literature search has been conducted in PubMed scientific literature database for nutrigenomics research studies on 38 genes included in nutrigenomics tests provided by various private genetic testing laboratories. Data were subsequently meta-analyzed to identify possible associations between the genes of interest and dietary intake and/or nutrient-related pathologies. Data analysis occurred according to four different models due to data sparsity and inconsistency. Data from 524,592 individuals (361,153 cases and 163,439 controls) in a total of 1,170 entries were obtained. Conflicting findings indicated that there was a great incompatibility regarding the associations (or their absence) identified. No specific-and statistically significant-association was identified for any of the 38 genes of interest. In those cases, where a weak association was demonstrated, evidence was based on a limited number of studies. As solid scientific evidence is currently lacking, commercially available nutrigenomics tests cannot be presently recommended. Notwithstanding, the need for a thorough and continuous nutrigenomics research is evident as it is a highly promising tool towards precision medicine

Can patient decision aids reduce decisional conflict in a de-escalation of breast radiotherapy clinical trial? The PRIMETIME Study Within a Trial implemented using a cluster stepped-wedge trial design

Background For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design.Methods PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect.Results Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video.Conclusion The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids

Can patient decision aids reduce decisional conflict in a de-escalation of breast radiotherapy clinical trial? The PRIMETIME Study Within a Trial implemented using a cluster stepped-wedge trial design.

BackgroundFor patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design.MethodsPDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect.ResultsFive hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video.ConclusionThe low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids

Novel genetic risk variants for pediatric celiac disease

Background: Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Methods: Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Results: Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G gt A, KIAA1109 c.2933T gt C and c. 4268_4269delCCinsTA, HoxB6 c.668C gt A, HoxD12 c.418G gt A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n=109) and Serbian (n=73) descent and their healthy counterparts (n=111 and n=32, respectively) indicated that HoxD12 c.418G gt A is more prevalent in celiac disease patients in the Serbian population (P lt 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0. 03). SLC9A4 c.1919G gt A and KIAA1109 c.2933T gt C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. Conclusions: The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Results: Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific diseaseassociated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. Conclusions: To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance

Study of the genetic basis of celiac disease in greek patients: extensions in immunogenetics

Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Several genetic, epidemiological, clinical, serological, and pathophysiological data indicate that celiac disease is associated with autoimmune thyroid disorders and in particular, Graves’ disease. Today, no clear nomogram is effective to allow for optimum disease management and patient stratification. Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Additionally, we explored the role of selected genomic variants resulting from extensive data mining for overlapping susceptibility between Graves’ disease and paediatric coeliac disease aiming for an immunogenetic model towards the identification of coeliac disease patients with an increased risk of developing Graves’ disease.The multi-step next-generation sequencing-based family genomics approach revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c. 4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c. 745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c. 418G>A is more prevalent in celiac disease patients in the Serbian population (P A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance.Moreover, extensive data mining, pathway analysis and literature review resulted in the selection of (CTLA4) c.*1421G>A, c.*1384G>A και c.49A>G, c. 49A>T, BACH2 c.-162+36253G>T και c.-274-41831G>C; c.-275+4001G> και IL23R c.956-8194A>G, c.956-819A>T. Data validation in pediatric celiac disease patients of Hellenic origin (n=109) and their ethnically matched counterparts (n=111) indicated that CTLA4 c.*1421G>A, c.*1384G>A is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0. 01). CTLA4 c.49A>G, c. 49A>T and BACH2 c.-162+36253G>T and IL23R c.-274-41831G>C; c.956-8194A>G, c.956-819A>T were more abundant in patients and BACH2 c.-275+4001G> T was more prevalent in healthy individuals; nevertheless, they failed to show statistical significance.The immunogenomics approach described herein may serve as a paradigm towards the identification of novel functional variants for theranostics and comorbidity biomarker discovery aiming to dissect the genetic basis of pediatric celiac disease in patients of Hellenic origin. Such risk variants may serve as the building block of a nomogram to optimize Graves’ and Celiac disease management and patient stratification.Η κοιλιοκάκη είναι μια σύνθετη χρόνια ανοσοδιαμεσολαβούμενη διαταραχή του λεπτού εντέρου. Σήμερα, η παθοβιολογία της νόσου είναι ασαφής, προκαλεί σύγχυση στη διαφορική διάγνωση, τη στρωματοποίηση των ασθενών και τη λήψη αποφάσεων στην κλινική. Αρκετά γενετικά, επιδημιολογικά, κλινικά, ορολογικά και παθοφυσιολογικά δεδομένα υποδεικνύουν ότι η κοιλιοκάκη σχετίζεται με αυτοάνοσες διαταραχές του θυρεοειδούς και ειδικότερα με τη νόσο του Graves. Σήμερα, κανένα σαφές νομόγραμμα δεν είναι αποτελεσματικό για να επιτρέπει τη βέλτιστη διαχείριση της νόσου και τη στρωματοποίηση των ασθενών.Στην παρούσα έρευνα, εφαρμόσαμε μια προσέγγιση επόμενης γενιάς αλληλούχησης και ανάλυση τύπου trio σε μια οικογένεια ελληνικής καταγωγής για τον εντοπισμό γενετικών παραλλαγών/ βιοδεικτών προδιάθεσης για τη κοιλιοκάκη. Επιπλέον, διερευνήσαμε το ρόλο επιλεγμένων γενετικών παραλλαγών, που προέκυψαν από εκτεταμένη εξόρυξη δεδομένων για την αλληλεπικαλυπτόμενη ευαισθησία (συννοσηρότητα) της νόσου του Graves και της κοιλιοκάκης στην παιδική ηλικία, με στόχο ένα ανοσογενετικό μοντέλο για τη βέλτιστη διαστρωμάτωση ασθενών με κοιλιοκάκη και αυξημένο κίνδυνο ανάπτυξης της νόσου του Graves.Η προσέγγιση αλληλούχησης επόμενης γενιάς αποκάλυψε έξι γενωμικές παραλλαγές πρωταρχικού ενδιαφέροντος: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C και c. 4268_4269delCCinsTA, HΟΧB6 c.668C>Α, HΟΧD12 c.418G>Α και NCK2 c.745_746delAAinsG, από τις οποίες η NCK2 c.745_746delAAinsG είναι καινοφανής. Η επικύρωση των δεδομένων σε ασθενείς με κοιλιοκάκη στην παιδική ηλικία ελληνικής (n = 109) και σερβικής (n = 73) καταγωγής και στους υγιείς ομολόγους τους (n = 111 και n = 32, αντίστοιχα) έδειξε ότι η HΟΧD12 c.418G>Α (P A και KIAA1109 c.2933T>C και c.4268_4269delCCinsTA ήταν πιο συχνές στους ασθενείς. Παρ 'όλα αυτά, δεν απέδειξαν στατιστική σημαντικότητα.Επιπλέον, η εκτεταμένη εξόρυξη δεδομένων και κειμένου, η ανάλυση των μοριακών μονοπατιών και η συστηματική ανασκόπηση της βιβλιογραφίας οδήγησαν στην επιλογή των CTLA4 c.*1421G>A, c.*1384G>A και c.49A>G, c. 49Α>Τ, BACH2 c.-162 + 36253G> Τ και c.-274-41831G> C; c.-275 + 4001G> και IL23R c.956-8194Α>G, c.956-819Α>Τ. Η επικύρωση των δεδομένων σε ασθενείς με κοιλιακή στην παιδική ηλικία ελληνικής καταγωγής (n = 109) και στους ομόλογούς τους (n = 111) έδειξε ότι η CTLA4 c.*1421G>A, c. *1384G>A είναι λιγότερο διαδεδομένη στους ασθενείς με κοιλιοκάκη έναντι των υγιών ατόμων (P = 0,01). Οι CTLA4 c.49A>G, c. 49Α>Τ, BACH2 c.-162 + 36253G> Τ και IL23R c.-274-41831G> C. c.956-8194A> G, c.956-819A> T ήταν πιο συχνές στους ασθενείς έναντι των υγιών ατόμων και η BACH2 c.-275 + 4001G>T ήταν πιο διαδεδομένη στα υγιή άτομα έναντι των παιδιατρικών ασθενών με κοιλιοκάκη. Εντούτοις, δεν απέδειξαν στατιστική σημασία.Η ανοσογονιδιωματική προσέγγιση που περιγράφεται στο παρόν πόνημα δύναται να αποτελέσει πρότυπο για την ταυτοποίηση νέων λειτουργικών παραλλαγών/ βιοδεικτών θερανοστικής και συννοσηρότητας, με σκοπό την αποσαφήνιση της γενετικής συνιστώσας της κοιλιοκάκης στην παιδική ηλικία στον ελληνικό πληθυσμό. Τέτοιες παραλλαγές κινδύνου μπορούν να χρησιμεύσουν ως δομικό στοιχείο ενός νομογράμματος για τη βελτιστοποίηση της διαχείρισης της κοιλιοκάκης και της νόσου του Graves και της στρωματοποίησης των ασθενών

Pharmacometabolomics informs viromics towards precision medicine

Nowadays, we are experiencing the big data era with the emerging challenge of single data interpretation. Although the advent of high-throughput technologies as well as chemo- and bio- informatics tools presents pan-omics data as the way forward to precision medicine, personalized health care and tailored-made therapeutics can be only envisaged when interindividual variability in response to/ toxicity of xenobiotics can be interpreted and thus, predicted. We know that such variability is the net outcome of genetics (host and microbiota) and environmental factors (diet, lifestyle, polypharmacy, microbiota) and for this, tremendous efforts have been made to clarify key-molecules from correlation to causality to clinical significance. Herein, we focus on the host-microbiome interplay and its direct and indirect impact on efficacy and toxicity of xenobiotics and we inevitably wonder about the role of viruses, as the least acknowledged ones. We present the emerging discipline of pharmacometabolomics-informed viromics, in which pre-dose metabotypes can assist modeling and prediction of interindividual response to/ toxicity of xenobiotics. Such features, either alone or in combination with host genetics, can power biomarker discovery so long as the features are variable among patients, stable enough to be of predictive value, and better than pre-existing tools for predicting therapeutic efficacy/ toxicity

Meta-analysis of genes in commercially available nutrigenomic tests denotes lack of association with dietary intake and nutrient-related pathologies

Nutrigenomics is an emerging discipline that aims to investigate how individual genetic composition correlates with dietary intake, as well as how nutrition influences gene expression. Herein, the fundamental question relates to the value of nutrigenomics testing on the basis of the currently available scientific evidence. A thorough literature search has been conducted in PubMed scientific literature database for nutrigenomics research studies on 38 genes included in nutrigenomics tests provided by various private genetic testing laboratories. Data were subsequently meta-analyzed to identify possible associations between the genes of interest and dietary intake and/or nutrient-related pathologies. Data analysis occurred according to four different models due to data sparsity and inconsistency. Data from 524,592 individuals (361,153 cases and 163,439 controls) in a total of 1,170 entries were obtained. Conflicting findings indicated that there was a great incompatibility regarding the associations (or their absence) identified. No specific—and statistically significant—association was identified for any of the 38 genes of interest. In those cases, where a weak association was demonstrated, evidence was based on a limited number of studies. As solid scientific evidence is currently lacking, commercially available nutrigenomics tests cannot be presently recommended. Notwithstanding, the need for a thorough and continuous nutrigenomics research is evident as it is a highly promising tool towards precision medicine