Veterinary medicine - Repository of PHD, master's thesis
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International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology
No full textBackground: Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
Objectives: This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B.
Methods: The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment.
Results: The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons.
Conclusion: Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B
Changes of cerebrospinal fluid pressure gradient in different body positions under experimental impairment of cerebrospinal fluid pathway: new insight into hydrocephalus development
No full textIt is generally accepted that hydrocephalus is a consequence of the disbalance between cerebrospinal fluid (CSF) secretion and absorption which should in turn lead to CSF pressure gradient development and ventricular enlargement. To test CSF pressure gradient role in hydrocephalus development, we experimentally caused CSF system impairment at two sites in cats. In the first group of animals, we caused Sylvian aqueduct obstruction and recorded CSF pressure changes pre and post obstruction at three measuring sites (lateral ventricle -LV, cortical-CSS and lumbar subarachnoid space -LSS) during 15 min periods and in different body positions over 360 degrees. In the second group of experiments, we caused cervical stenosis by epidural plastic semiring implantation and monitored CSF pressure changes pre and post stenosis implantation at two measuring sites (lateral ventricle and lumbar subarachnoid space) during 15 min periods in different body positions over 360 degrees. Both groups of experimental animals had similar CSF pressures before stenosis or obstruction at all measuring points in the horizontal position. During head-up verticalization, CSF pressures inside the cranium gradually became more subatmospheric with no significant difference between LV and CSS, as they are measured at the same hydrostatic level, while CSF pressure inside LSS became more positive, causing the development of a large hydrostatic gradient between the cranial and the spinal space. With cervical stenosis, CSF pressure inside the cranium is positive during head-up verticalization, while in cats with aqueductal obstruction CSF pressure inside the CSS remains negative, as it was during control period. Concomitantly, CSF pressure inside LV becomes less negative, thus creating a small hydrostatic gradient between LV and CSS. Since CSF pressure and gradient changes occur only by shifting body position from the horizontal plane, our results indicate that cervical stenosis in a head-up vertical position reduces blood perfusion of the whole brain, while aqueductal obstruction impairs only the perfusion of the local periventricular brain tissue. It seems that, for evolutionary important bipedal activity, free craniospinal communication and good spinal space compliance represent crucial biophysical parameters for adequate cerebral blood perfusion and prevention of pathophysiological changes leading to the development of hydrocephalus
Enhancement of Vascularization and Ovarian Follicle Survival Using Stem Cells in Cryopreserved Ovarian Tissue Transplantation—A Systematic Review
No full textThe increase in cancer survival rates has put a focus on ensuring fertility preservation procedures for cancer patients. Ovarian tissue cryopreservation presents the only option for prepubertal girls and patients who require immediate start of treatment and, therefore, cannot undergo controlled ovarian stimulation. We aimed to provide an assessment of stem cells’ impact on cryopreserved ovarian tissue grafts in regard to the expression of growth factors, angiogenesis promotion, tissue oxygenation, ovarian follicle survival and restoration of endocrine function. For this systematic review, we searched the Scopus and PubMed databases and included reports of trials using murine and/or human cryopreserved ovarian tissue for transplantation or in vitro culture in combination with mesenchymal stem cell administration to the grafting site. Of the 1201 articles identified, 10 met the criteria. The application of stem cells to the grafting site has been proven to support vascular promotion and thereby shorten the period of tissue hypoxia, which is reflected in the increased number of remaining viable follicles and faster recovery of ovarian endocrine function. Further research is needed before implementing the use of stem cells in OT cryopreservation and transplantation procedures in clinical practice. Complex ethical dilemmas make this process more difficult
Expression and prognostic significance of PD-L1 and NY-ES01 in gallbladder carcinoms
No full textCilj. Karcinom žučnog mjehura je rijetka zloćudna bolest s vrlo visokom smrtnošću, obično zbog dijagnosticiranja u uznapredovalom stadiju bolesti. Cilj ovog istraživanja bio je procijeniti izraženost NY-ESO1 i PD-L1 i njihov utjecaj na prognozu bolesnika s karcinomom žučnog mjehura.
Materijali i metode. Imunohistokemijskim bojenjem odredili smo izraženost NY-ESO1 u tumoru i PD-L1 u tumorskim i intratumorskim imunološkim stanicama u 57 bolesnika s karcinomom žučnog mjehura.
Rezultati. Karcinomi žučnog mjehura izražavaju NY-ESO1 u 68,4 % slučajeva. PD-L1 je izražen u 45,6 % slučajeva, većinom u intratumorskim imunološkim stanicama (35,1%) a rjeđe u tumorskim stanicama (10,5 %). Izraženost NY-ESO1 je u negativnoj korelaciji s izraženošću PD-L1 u imunološkim stanicama (rs = - 0,313; p = 0,021). NY-ESO1 nije pokazao povezanost s bilo kojim kliničko-patološkim parametrom ili ukupnim doživljenjem. Izraženost PD-L1 u imunološkim stanicama bila je značajno viša u tumorima s perineuralnom invazijom (rs = 0,318; p = 0,018) i višim kliničkim stadijem bolesti (rs = 0,339; p = 0,013), ali nije pokazala povezanost s ukupnim doživljenjem. U našem istraživanju, medijan ukupnog doživljenja bolesnika s karcinomom žučnog mjehura je 7 mjeseci, sa stopom petogodišnjeg doživljenja od 10 %. Petogodišnje doživljenje od 42 % postignuto je jedino u bolesnika s karcinomom kliničkog stadija I. Rizik od smrti unutar 12 mjeseci je 5,15 puta veći u slučaju veće dubine invazije tumora (pT 3/4). Također je rizik 2,5 puta veći za bolest dijagnosticiranu u kliničkim stadijima višim od stadija I te dvostuko veći u slučaju višeg histološkog gradusa tumora.
Zaključak. Ovim istraživanjem nije dokazana povezanost PD-L1 i NY-ESO1 s prognozom bolesti. Značajan postotak karcinoma imao je izražene istraživane proteine, stoga bi, prema dosadašnjim spoznajama iz drugih studija, mogli biti mete za ciljanu imunoterapiju. U tom smjeru svakako su potrebna dodatna istraživanja na većem broju uzoraka karcinoma žučnog mjehura.Aim. Gallbladder cancer is a rare malignancy with a very high mortality, usually due to diagnosis in an advanced stage of the disease. Therefore, the aim of this study was to evaluate the clinical significance of NY-ESO1 and PD-L1 and their impact on the prognosis of patients with gallbladder cancers.
Materials and methods. Using immunohistochemical staining, we determined the expression of NY-ESO1 in tumor and PD-L1 in both tumor and intratumoral immune cells in 57 patients with gallbladder cancer.
Results. Gallbladder cancers express NY-ESO1 in 68.4 % of cases. PD-L1 was expressed in 45.6 % of cases, mostly in intratumoral immune cells (35 %) and less often in tumor cells (10.5 %). The expression of NY-ESO1 is negatively correlated with the expression of PD-L1 in immune cells (rs = - 0.313; p = 0.021). NY-ESO1 did not show association with any clinicopathological parameters or overall survival. PD-L1 expression in immune cells was significantly higher in tumors with perineural invasion (rs = 0.318; p = 0.018) and higher clinical stage of disease (rs = 0.339; p = 0.013), but did not show an association with overall survival. In our study, the median overall survival of patients with gallbladder cancer was 7 months, with a 5-year survival rate of 10 %. Five-year survival of 42% was achieved only for patients with clinical stage I cancer. The risk of death within 12 months is 5.15 times higher in case of deeper tumor invasion (pT 3/4); 2.5 times higher for the disease diagnosed in clinical stages higher than stage I and twice higher in the case of a higher histological tumor grade.
Conclusion. This study did not prove a correlation between PD-L1 and NY-ESO1 with the prognosis of gallbladder cancer. A significant percentage of cancers expressed investigated proteins, which, according to previous findings from other studies, could be candidates for targeted immunotherapy. In this direction, additional research on gallbladder cancer is needed
Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease
No full textBiallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity
Corneal Biomechanics and Other Factors Associated with Postoperative Astigmatism after Cataract Surgery
No full textThis study aimed to investigate the impact of the cornea’s biomechanical properties, corneal hysteresis (CH), and corneal resistance factor (CRF) on postoperative astigmatism after cataract surgery and determine the other factors that influence it. Forty eyes of 40 patients (13M/27F; the median age of 74) were included in this prospective study, underwent 2.75 mm incision cataract surgery, and were followed for 30 days. Visits were scheduled at baseline before surgery (V0), the 1st (V1), the 7th (V2), and the 30th (V3) postoperative days. The main parameters estimated and analyzed with Statistica® 14.0.1 were CH, CRF, astigmatism diopter, and axis. Following the cataract surgery, the CH did not significantly change during the study visits (p = 0.109). However, there was a significant change in the CRF from baseline during the study visits (per protocol set) (p = 0.002). After a slight but insignificant increase from V0 to V1, post hoc analysis found a significant decrease in the mean CRF from V1 to V2 (p = 0.049) with no substantial change from V2 to V3. According to the post hoc analysis, the median astigmatism diopter increased significantly only from V0 to V1 (p = 0.001) and slightly but not significantly decreased to the end of the study with the achievement of a near-baseline value. The main predictors for the final astigmatism diopter (R2 = 0.898) obtained by stepwise regression analysis were its values at V0, V1, and V2 (p < 0.001). The CRF at V1 was marginally significant, with a negative parameter estimate of −0.098303 (p = 0.0623). In conclusion, there was no correlation between preoperative CH and CRF and postoperative astigmatism using 2.75 mm incision cataract surgery. However, the final astigmatism diopter’s main predictors were its baseline values before cataract surgery, the first, and the seventh postoperative days
Diverse roles of Primary Health Care in COVID-19 vaccination across 28 European countries – Insights from the Eurodata study
No full textBackground: The COVID-19 vaccination campaign in several European countries involved collaboration between public health and Primary Health Care (PHC).
Objective: To highlight the role of PHC professionals in the COVID-19 vaccination rollout, specifically in terms of vaccine administration, communication and contributing to vaccination population coverage.
Methods: A descriptive retrospective study of the COVID-19 vaccination campaign across 28 European countries was conducted, covering data from December 2020 to November 2021. Data were collected by key informants recruited from each country, who were health professionals involved in their national vaccination campaigns. Utilising an ad-hoc semi-structured questionnaire, information was gathered on organisation, communication strategies, priority groups, vaccine types, and vaccination pathways in PHC.
Results: PHC participated in communication strategies in 10 out of 28 countries, and vaccination was voluntary in most of them. The priority groups for vaccination varied across Europe, and the availability of vaccines in PHC differed between countries within the European Union (EU) and non-EU countries. The BioNTech Pfizer vaccine was the most widely available vaccine in most countries, followed by Moderna and AstraZeneca. PHC administered COVID-19 vaccines to the population, being the nurses the most involved, followed by general practitioners. Vaccination appointments were available online in 18/28 or by phone in 15/28, direct appointments at health centres were available in 8/28. In several countries, healthcare professionals who administered vaccines were given extra compensation for their role.
Conclusion: PHC professionals played a crucial role in the successful distribution and administration of COVID-19 vaccines in European countries
The Association between the Firmicutes/Bacteroidetes Ratio and Body Mass among European Population with the Highest Proportion of Adults with Obesity: An Observational Follow-Up Study from Croatia
No full textBackground/Objectives: The phyla Firmicutes and Bacteroidetes are the main constituents of the gut microbiota. An imbalance in the gut microbiota is a sign of dysbiosis, and the Firmicutes-to-Bacteroidetes ratio has been proposed to be a marker of it, especially in the context of obesity. Since Croatia is the country with one of the highest obesity rates in Europe, a pilot observational study was conducted. The aim of the study was to investigate the validity of this potential biomarker in a methodological study using sample processing, DNA sequence analysis and characterization of recruited participants, including various health factors. Methods: A study involving Croatian population was conducted. Participants age, body weight, gender, health history and lifestyle factors were recorded. Gut microbiota composition was analyzed using 16S rRNA sequencing. The F/B ratio was calculated and evaluated in the context of health factors. Statistical analysis was performed to detect the possible association of F/B ratio and excess body weight (kg) and possible impact of certain lifestyle factors. Results: No association between the F/B ratio and excess body weight (kg) was found. Excess body weight was significantly associated with higher age, male gender, and history of appendectomy. No significant health predictors of the F/B ratio were found, but weight gain was positively associated with a higher average F/B ratio. Conclusions: Although this study could not confirm the predictive value of the F/B ratio or any other phyla-related biomarker for excess body weight in the study population, it demonstrated interesting insights into the obesity-associated gut microbiota
Platelet transfusion in neonatal intensive care units of 22 European countries: a prospective observational study
No full textBackground: Platelet transfusions are given to preterm infants with severe thrombocytopenia aiming to prevent haemorrhage. The PlaNeT2/MATISSE trial revealed higher rates of mortality and/or major bleeding in preterm infants receiving prophylactic platelet transfusions at a platelet count threshold of 50 × 109/L compared to 25 × 109/L. The extent to which this evidence has been incorporated into clinical practice is unknown, thus we aimed to describe current neonatal platelet transfusion practices in Europe.
Methods: We performed a prospective observational study in 64 neonatal intensive care units across 22 European countries between September 2022 and August 2023. Outcome measures included observed transfusion prevalence rates (per country and overall, pooled using a random effects Poisson model), expected rates based on patient-mix (per country, estimated using logistic regression), cumulative incidence of receiving a transfusion by day 28 (with death and discharge considered as competing events), transfusion indications, volumes and infusion rates, platelet count triggers and increment, and adverse effects.
Findings: We included 1143 preterm infants, of whom 71 (6.2%, [71/1143]) collectively received 217 transfusions. Overall observed prevalence rate was 0.3 platelet transfusion days per 100 admission days. By day 28, 8.3% (95% CI: 5.5-11.1) of infants received a transfusion. Most transfusions were indicated for threshold (74.2%, [161/217]). Pre-transfusion platelet counts were above 25 × 109/L in 33.1% [53/160] of these transfusions. There was significant variability in volume and duration.
Interpretation: The restrictive threshold of 25 × 109/L is being integrated into clinical practice. Research is needed to explore existing variation and generate evidence for various aspects including optimal volumes and infusion rates
Advantages of Ultrafast™ ultrasound in the screening for renal artery disease
No full textAim: Renal artery disease is the most common cause of secondary hypertension worldwide. B-mode and Doppler ultrasound are considered the modalities of choice for the imaging of the renal arteries. However, an adequate examination can be plagued by difficulties in patients with unfavorable anatomy. UltraFast™ ultrasound is faster, performed with higher frame rates, and enables prospective and retrospective data analysis with quantification of flow data in the obtained image, so it may be able to resolve some of the difficulties encountered during conventional ultrasound examinations in patients with suspected renal artery disease.
Material and methods: Comparison of the duration of conventional and UltraFast™ Doppler examinations of segmental renal arteries was performed on 52 young, healthy volunteers. Duration times were summarized using the median and interquartile range, and comparisons between the two methods were performed using the Wilcoxon test for paired samples.
Results: The duration of UltraFast™ ultrasound examinations was significantly shorter in comparison to conventional ultrasound for both kidneys and in total (p <0.001, median difference in duration 65 s, median 64% shorter duration of analysis), while both conventional and UltraFast™ ultrasound examinations demonstrated consistent velocity measurements with very high correlation (Rho = 0.94, p <0.001).
Conclusions: The study provides evidence that UltraFast™ ultrasound is faster than conventional Doppler ultrasonography for the assessment of renal artery disease in healthy adults without a history of renal disease. The findings have important implications for clinical practice, as they suggest that UltraFastTM imaging could offer a more efficient and time-saving approach to vascular imaging in patients with suspected renal artery disease