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Abstract Objective We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. Methods In this cross‐sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. Results Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p

Abstract Introduction Prevalence of cancer patients is dramatically increasing. We aimed at quantifying the oncology workload generated by each new cancer patient in the two years following first consultation. Methods In this record-based retrospective study, we retrieved data of all newly diagnosed patients treated at the Oncology Department of Udine Academic Hospital between 01.01.2012 and 31.12.2017. We calculated mean number and standard deviation of the activity type generated by each new cancer patient during the following 2 years. Results Seven thousand four hundred fifty-two cancer patients generated a total of 85,338 clinical episodes. The two-years mean number of oncology episodes generated was 11.31 (i.e., for every 1,000 new cancer patients, 11,310 oncology activities are generated overall in the following two-year lapse). Patients with advanced disease generated the highest workload (24.3; SD 18.8) with a statistically significant difference compared to adjuvant and follow-up patients (p

Abstract Background Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. Methods ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. Discussion Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. Trial registration This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

The goal of this paper is to describe the teaching of initial multiplication concepts and skills, up to the multiplication table, in the Croatian educational system. As Stiegler and Hiebert (1999) concluded, teaching is a complex system rooted in a cultural script of a given society. To describe it without ignoring certain features of it that appear to be self-evident to an insider, it is necessary to step out of this cultural frame. For that reason, we study the teaching of initial multiplication in Croatia by comparing Croatian mathematical textbooks with textbooks from Singapore, Japan, and England. For the textbook analysis, we adapt the framework of Charalambous, Delaney, Hsu, and Mesa that examines a textbook as an environment for the construction of knowledge of a single mathematical concept. The analysis provides evidence that practice and automation are at the centre of the initial learning of multiplication in Croatia. The meaning of multiplication usually is not clear, and pupils are not provided additional tools for developing understanding, nor they are encouraged to use different calculation strategies in a flexible manner. The study also indicates that Croatian textbooks present mathematics as a practice that is closed and pre-given, restricted to the one and the only right way through it.

The recent advances in remote sensing provide opportunities for estimating the parameters of conceptual hydrologic models more reliably. However, the question of whether and to what extent the use of satellite data in model calibration may assist in transferring model parameters to ungauged catchments has not been fully resolved. The aim of this study is to evaluate the efficiency of different methods for transferring model parameters obtained by multiple-objective calibrations to ungauged sites and to assess the model performance in terms of runoff, soil moisture, and snow cover predictions relative to existing regionalization approaches. The model parameters are calibrated to daily runoff, satellite soil moisture (Advanced Scatterometer – ASCAT), and snow cover (Moderate Resolution Imaging Spectroradiometer – MODIS) data. The assessment is based on 213 catchments situated in different physiographic and climate zones of Austria. For the transfer of model parameters, eight methods (global and local variants of arithmetic mean, regression, spatial proximity, and similarity) are examined in two periods, i.e., the period in which the model is calibrated (2000–2010) and an independent validation period (2010–2014). The predictive accuracy is evaluated by the leave-one-out cross-validation. The results show that the method by which the model is calibrated in the gauged catchment has a larger impact on runoff prediction accuracy in the ungauged catchments than the choice of the parameter transfer method. The best transfer methods are global and local similarity and the kriging approach. The performance of the transfer methods differs between lowland and alpine catchments. While the soil moisture and snow cover prediction efficiencies are higher in lowland catchments, the runoff prediction efficiency is higher in alpine catchments. A comparison of the model transfer methods, based on parameters calibrated to runoff, snow cover, and soil moisture with those based on parameters calibrated to runoff, only indicates that the former outperforms the latter in terms of simulating soil moisture and snow cover. The performance of simulating runoff is similar, and the accuracy depends mainly on the weight given to the runoff objective in the multiple-objective calibrations.

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2ΔNRR-DEL2 deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTAT, G>A for rs2453058) or destroy (CTCGT, A>G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient NOTCH2 gene variant (*1A01) which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent NOTCH2 variant (*1a4) that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 (*1A01) and rs5025718 (*1a4) leads to recombined NOTCH2 alleles with altered BPS patterns in NOTCH2*1A01/*1a4 CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering. [ABSTRACT FROM AUTHOR]

Background/Objectives: Endometriosis is a chronic condition that affects 6–10% of women of reproductive age, with pain and infertility being its primary symptoms. The most common aspects of pain are overall pelvic pain, dysmenorrhea, and dyspareunia. Our aim was to compare the available medical treatments for endometriosis-related pain. Methods: A systematic search was conducted in three medical databases to assess available drug options for pain management. Randomized controlled trials (RCTs) investigating various medical treatments for endometriosis-related pain on different pain scales were included. Results were presented as p-scores and, in cases of placebo controls, as mean differences (MD) with 95% confidence intervals (CI). From the available data, a network meta-analysis was carried out. Results: The search yielded 1314 records, of which 45 were eligible for data extraction. Eight networks were created, and a total of 16 treatments were analyzed. The highest p-score, meaning greatest pain relief (p-score: 0.618), for the treatment of dysmenorrhea was achieved using gonadotropin-releasing hormone (GnRH) agonists for 3 months on a scale of 0–100. Additionally, a p-score of 0.649 was attained following a 6-month treatment with GnRH agonists combined with hormonal contraceptives (CHCs). In the case of dyspareunia on a scale of 0–100 following 3 months of treatment, CHCs (p-score: 0.805) were the most effective, and CHCs combined with aromatase inhibitors (p-score: 0.677) were the best treatment option following 6 months of treatment. In the case of overall pelvic pain, CHCs (p-score: 0.751) yielded the highest p-score on a scale of 0–100 following 3 months of treatment, and progestins combined with aromatase inhibitors (p-score: 0.873) following 6 months of treatment. Progestins (p-score: 0.901) were most effective in cases of overall pelvic pain on a scale of 0–3 following 3 months of treatment. Conclusions: Our network meta-analysis showed that in cases of dysmenorrhea, GnRH agonists supplemented with CHCs reduced pain the most following 3 months of treatment. Regarding dyspareunia CHCs were most effective, and in the case of overall pelvic pain, CHCs or progestins combined with aromatase inhibitors yielded the most desirable results. [ABSTRACT FROM AUTHOR]

One of the critical processes in human reproduction that is still poorly understood is implantation. The implantation of an early human embryo is considered a significant limitation of successful pregnancy. Therefore, researchers are trying to develop an ideal model of endometrium in vitro that can mimic the endometrial micro-environment in vivo as much as possible. The ultimate goal of endometrial modeling is to study the molecular interactions at the embryo-maternal interface and to use this model as an in vitro diagnostic tool for infertility. Significant progress has been made over the years in generating such models. The first experiments of endometrial modeling involved animal models, which are undoubtedly valuable, but at the same time, their dissimilarities with human tissue represent a significant obstacle to further research. This fact led researchers to develop basic monolayer coculture systems using uterine cells obtained from biopsies and, later on, complex and multilayer coculture models. With successful tissue engineering methods and various cultivation systems, it is possible to form endometrial two-dimensional (2D) models to three-dimensional (3D) organoids and novel assembloids that can recapitulate many aspects of endometrial tissue architecture and cell composition. These organoids have already helped to provide new insight into the embryo-endometrium interplay. The main aim of this paper is a comprehensive review of past and current approaches to endometrial model generation, their feasibility, and potential clinical application for infertility treatment. [ABSTRACT FROM AUTHOR]

Insulin is preferred as the first-line agent for glucose management of gestational diabetes mellitus and type 2 diabetes in pregnancy when nutritional and lifestyle modifications are unable to achieve pregnancy-specific glucose targets. Individual heterogeneity in defects of insulin secretion or sensitivity in liver and muscle, unique genetic influences on pregnancy glycemic regulation, and variable cultural and lifestyle behaviors that affect meal, activity, sleep, and occupational schedules necessitate a personalized approach to insulin regimens. Newer insulin preparations have been developed to mimic the physiologic release of endogenous insulin, maintaining appropriate basal levels to cover hepatic gluconeogenesis and simulate the rapid, meal-related, bolus rise of insulin. Such physiologic basal-bolus dosing of insulin can be administered safely, achieving tighter glycemic control while reducing episodes of hypoglycemia. Insulin initiation and titration require understanding the pharmacodynamics of different insulin preparations in addition to a patient's glycemic profiles, effect of variable nutritional intake and mealtimes, physical activity, stress, timing of sleep cycles, and cultural habits. Educating and empowering patients to learn how their glucose responds to insulin, portion and content of meals, and physical activity can increase personal engagement in therapy, flexibility in eating patterns, and improved glycemic control. This Clinical Expert Series article is focused on optimizing insulin management (initiation, dosing, and titration) of gestational and type 2 diabetes in pregnancy. [ABSTRACT FROM AUTHOR]

Summary: Our observational study analysed fungal infection frequency within cohorts with versus without antifungal prophylaxis (AFP) among newly diagnosed first‐line venetoclax and azacitidine (VEN + AZA)‐treated acute myeloid leukaemias in Czech, Austrian and Slovak haematology centres. Among 186 patients, 85 (46%) received antifungal prophylaxis, while 101 (54%) received no prophylaxis. Fungal infections occurred in 1/85 patients with prophylaxis (1%) and 5/101 patients without prophylaxis (5%) (p = 0.222). No significant difference was recorded between cohorts with and without AFP in terms of death rate (p = 0.296) and overall survival (p = 0.844). In conclusion, most infections were not severe, developing during the first treatment‐cycle and did not affect patients' overall outcome. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe handbike configurations and the prevalence of experienced sitting and riding-related problems among recreational handcyclists training for a mountain time trial (HandbikeBattle). In this cross-sectional study, 150 participants of the HandbikeBattle, who used an arm-power (recumbent) handbike, filled out a questionnaire (on comfort, stability and power generation) while handbike characteristics were measured. Crank width was variable among handcyclists and was wider than the shoulder width (median crank/shoulder width ratio: 1.19). About 60% of the participants found sitting in the handbike never fatiguing or painful and 74–76% indicated to sit stable in the handbike when sitting or when generating power. About 80% of the participants thought that their pedal position was optimal. Although the overall scores regarding sitting position and riding settings were high (both questions median: 8.0 on 1.0–10.0 scale), 50% and 31% of the participants, respectively, believed that their sitting position and riding settings could be improved. In addition, 10% of the participants thought that the configuration could lead to an injury and had an injury at the time of filling out the questionnaire. It can be concluded that although the majority of the participants seemed to be satisfied with their handbike configurations a large variety in handbike configurations was seen. There is a need for the development of evidence-based guidelines for handbike fitting in the future. IMPLICATIONS FOR REHABILITATION: A large variety in handbike configurations is seen in recreationally-active handcyclists. Although the majority of the recreationally-active handcyclists seemed to be satisfied with their handbike configurations, 31–50% of them thought that their handbike configuration could be improved. Evidence-based guidelines for handbike fitting should be developed in the future. [ABSTRACT FROM AUTHOR]

Introduction: The prenatal diagnosis of congenital heart disease (CHD) is a traumatic event that can cause expectant parents to experience anxiety, depression, and toxic stress. Prenatal exposure to stress may impact neonatal postoperative outcomes. In addition, expectant parents may have other psychosocial stressors that may compound maternal stress. We investigated the relationship between stress in pregnancies complicated by prenatally diagnosed CHD and their neonatal outcomes. Methods: A pilot retrospective cohort study of pregnancies with prenatally diagnosed critical CHD (2019–2021) was performed. The collected data included pregnancy characteristics and neonatal and postoperative outcomes (including the need for exogenous corticosteroid treatment (ECT)). In order to quantify prenatal stressors, a composite prenatal stress score (PSS) was established and utilized. Results: In total, 41 maternal–fetal dyads were evaluated. Thirteen (32%) neonates had single-ventricle anatomy. The need for ECT after CHD surgery was associated with higher pregnant patient PSS (p = 0.01). PSS did not correlate with birthweight, infection, or hypoglycemia in the neonatal period. Conclusions: Prenatal stress is multifactorial; higher PSS is correlates with post-bypass ECT, suggesting that a stressful intrauterine environment may be associated with worse neonatal postoperative outcomes.