Miracle-dz/UniFAR-FTUs huggingface dataset:
Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

The development of high‐titre inhibitory antibodies (inhibitors) against factor VIII (FVIII) remains a challenge in the management of patients with haemophilia A (HA). Patients with high‐titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction (ITI), utilizing repeated infusions of FVIII, is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII‐specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII. Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half‐life, management of non‐responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI.
Plug-in Regularized Estimation of High-Dimensional Parameters in Nonlinear Semiparametric Models

We develop a theory for estimation of a high-dimensional sparse parameter $\theta$ defined as a minimizer of a population loss function $L_D(\theta,g_0)$ which, in addition to $\theta$, depends on a, potentially infinite dimensional, nuisance parameter $g_0$. Our approach is based on estimating $\theta$ via an $\ell_1$-regularized minimization of a sample analog of $L_S(\theta, \hat{g})$, plugging in a first-stage estimate $\hat{g}$, computed on a hold-out sample. We define a population loss to be (Neyman) orthogonal if the gradient of the loss with respect to $\theta$, has pathwise derivative with respect to $g$ equal to zero, when evaluated at the true parameter and nuisance component. We show that orthogonality implies a second-order impact of the first stage nuisance error on the second stage target parameter estimate. Our approach applies to both convex and non-convex losses, albeit the latter case requires a small adaptation of our method with a preliminary estimation step of the target parameter. Our result enables oracle convergence rates for $\theta$ under assumptions on the first stage rates, typically of the order of $n^{-1/4}$. We show how such an orthogonal loss can be constructed via a novel orthogonalization process for a general model defined by conditional moment restrictions. We apply our theory to high-dimensional versions of standard estimation problems in statistics and econometrics, such as: estimation of conditional moment models with missing data, estimation of structural utilities in games of incomplete information and estimation of treatment effects in regression models with non-linear link functions.
On Power and Rate Allocation for Coded Uplink NOMA in a Multicarrier System

In this paper, we propose a simple power and rate allocation scheme for uplink non-orthogonal multiple access based on a multicarrier system when a practical modulation and coding scheme is employed at each user. Since information-theoretic approaches with asymptotic settings are not considered, the proposed power and rate allocation scheme is able to provide a guaranteed performance with any practical block codes of finite length in terms of the probability of code word error. For the performance prediction in the power and rate allocation with given channel realizations, we employ non-asymptotic approaches for bounds on the probability of code word error. Through simulation results, we can confirm that the probability of code word error can be lower than or close to the target error rate using the proposed power and rate allocation.
A Patient-Centered Activity Regimen Improves Participation in Physical Activity Interventions in Advanced-Stage Lung Cancer

Introduction: Physical activity (PA) is a potential therapy to improve quality of life in patients with advanced-stage lung cancer (LC), but no PA regimen has been shown to be beneficial, clinically practical, and sustainable. We sought to test the hypothesis that a patient-centered activity regimen (PCAR) will improve patient participation and PA more effectively than weekly phone calls. Methods: In patients with advanced-stage LC, we implemented a walking-based activity regimen and motivated patients via either weekly phone calls (n = 29; FitBit Zip accelerometer) or PCAR (n = 15; FitBit Flex, an educational session, and twice-daily gain-framed text messages). Data collection over a 4-week period was compared, and a repeated-measures, mixed-effects model for activity level was constructed. Results: Subjects receiving PCAR more frequently used the device (100% vs 79%) and less frequently had missing data (11% vs 38%). “More active” and “less active” groups were created based on mean step count in the first week. “Less active” patients in the PCAR group increased their PA level, whereas PA level fell in the “more active” group. Most subjects found PCAR helpful (92%) and would participate in another activity study (85%). Discussion: Compared with weekly phone calls, PCAR has higher patient participation, is more likely to improve PA in “less active” subjects, and has high patient satisfaction. A multifaceted PA regimen may be a more efficacious mechanism to study PA in advanced LC. PCAR should be used in a randomized controlled trial to evaluate for improvements in symptom burden, quality of life, and mood.
Measuring Unfair Inequality: Reconciling Equality of Opportunity and Freedom from Poverty

Rising income inequalities are widely debated in public and academic discourse. In this paper, we contribute to this debate by proposing a new family of measures of unfair inequality. To do so, we acknowledge that inequality is not bad per se, but that its underlying sources need to be taken into account. Thereby, this paper is the first to reconcile two prominent fairness principles, namely equality of opportunity and freedom from poverty, into a joint measure of unfair inequality. Two empirical applications provide important new insights on the development of unfair inequality both over time (in the US) and across countries (in Europe). First, unfair inequality shows different time trends and country rankings compared to total inequality. Second, average unfair inequality doubles when complementing the ideal of an equal opportunity society with poverty aversion. Furthermore, we show that an exclusive focus on top incomes may misguide fairness judgments.
pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma

ABSTRACT Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.
Revascularization vs. Medical Therapy for Coronary Chronic Total Occlusions in Patients With Chronic Kidney Disease.

BACKGROUND We investigated whether the outcome of revascularization differed from the outcome of medical therapy in chronic kidney disease (CKD) and non-CKD patients with chronic total occlusion (CTO). Methods and Results:A total of 2,010 patients with CTO who underwent revascularization (n=1,355), including percutaneous coronary intervention (n=878) and coronary artery bypass grafting (n=477), or had medical therapy alone (n=655) were examined. The primary outcome was all-cause death during follow-up. Among the non-CKD patients (n=1,679), revascularization had a lower incidence of all-cause death (adjusted hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41-0.72, P<0.001) compared with medical therapy. Among the CKD patients (n=331), the difference in the incidence of all-cause death was not as marked between the 2 treatments (adjusted HR 0.71, 95% CI 0.48-1.06, P=0.09). There was a significant interaction between kidney function and treatment strategy (revascularization vs. medical therapy) on all-cause death (P for interaction=0.014). CONCLUSIONS Based on the clinical outcomes, in CTO patients with preexisting CKD, revascularization via PCI or bypass surgery might not be as effective as in non-CKD patients.
Distinct age-associated molecular profiles in acute myeloid leukemia defined by comprehensive clinical genomic profiling

Large scale comprehensive genomic profiling (CGP) has led to an improved understanding of oncogenic mutations in acute myeloid leukemia (AML), as well as identification of alterations that can serve as targets for potential therapeutic intervention. We sought to gain insight into age-associated variants in AML through comparison of extensive DNA and RNA-based GP results from pediatric and adult AML. Sequencing of 932 AML specimens (179 pediatric (age 0–18), 753 adult (age ≥ 19)) from diagnostic, relapsed, and refractory times points was performed. Comprehensive DNA (405 genes) and RNA (265) sequencing to identify a variety of structural and short variants was performed. We found that structural variants were highly prevalent in the pediatric cohort compared to the adult cohort (57% vs. 30%; p < 0.001), with certain structural variants detected only in the pediatric cohort. Fusions were the most common structural variant and were highly prevalent in AML in very young children occurring in 68% of children < 2 years of age. We observed an inverse trend in the prevalence of fusions compared to the average number of mutations per patient. In contrast to pediatric AML, adult AML was marked by short variants and multiple mutations per patient. Mutations that were common in adult AML were much less common in the adolescent and young adult cohort and were rare or absent in the pediatric cohort. Clinical CGP demonstrates the biologic differences in pediatric vs. adult AML that have significant therapeutic impacts on prognosis, therapeutic allocation, disease monitoring, and the use of more targeted therapies.
Li-Fi and Wi-Fi with common backhaul: Coordination and resource allocation

Visible light communication (VLC)-also known as light fidelity (Li-Fi)-networks will play an important role in the near future, since they will provide full coverage and improved data rates for indoor wireless applications. In this paper, the coexistence of Li-Fi and Wi-Fi networks is investigated for the multi-user scenario, under the practical assumption that both of them are served by the same backhaul network (e.g., optical fiber). More specifically, we study the resource allocation and coordination problems by maximizing the proportional fairness of all users. To do so, we formulate and solve an optimization problem for the power allocation of the hybrid Li-Fi/Wi-Fi scenario, under the constraint of the common backhaul. Computer simulation results are provided to illustrate the effectiveness of the proposed analysis.
Transfusion Management of Incident Dialysis Patients in Canada: A Prospective Observational Study

Background: Several studies have demonstrated harm associated with using erythropoiesis-stimulating agents (ESA) to achieve higher hemoglobin (Hb) levels. Subsequently, more conservative use of ESAs has changed anemia therapy in patients with chronic renal failure. Objective: The objectives were to identify transfusion rates in hemodialysis (HD) patients during the first year of therapy, to identify factors associated with the probability of transfusion, describe reasons for the transfusions, and identify the Hb values associated with each transfusion. An exploratory objective was to describe the age of red blood cell transfusions. Design: This was a multicenter prospective observational cohort study. Setting: There were 12 study sites in 5 Canadian provinces. The study was performed from 2012 to 2014. Methods: The study patients were adult incident chronic HD patients in these centers. Patients with acute kidney injury, peritoneal dialysis, and planned transfer to satellite units were excluded. Patients had to receive at least 1 month of chronic HD to be eligible. Data for 3 months prior to HD were obtained by retrospective chart review. Prospectively, charts were reviewed monthly for 12 months for data abstraction. Results: There were 314 patients enrolled and 79.9% completed 12 month follow-up. Ninety-four (29.9%) patients received at least 1 unit of blood. During the first 90 days, the transfusion episode rate was 148.4 per 100 patient-years compared with 62.6 per 100 patient-years post 90 days. The most frequent indication was a low Hb value (92%) with gastrointestinal bleeding, surgical blood loss, and fatigue accounting for 9.9%, 8.6%, and 4.5%, respectively. Some patients had >1 indication. The mean Hb values prior to transfusion episodes ranged from 75.3 to 78.6 g/L. Cox regression analysis on time to first transfusion and time to first hospitalization/death both showed an association with inpatient initiation of HD. Some 37.5% initiated HD as an inpatient and differed from those starting as an outpatient. They had less predialysis care and laboratory data suggested more inflammation. The mean and median ages of the blood units transfused were 24.9 (SD = 10.0) and 23 days (interquartile range = 17-33). Conclusions: This work reported the blood transfusion rate in incident HD patients in Canada during a period associated with conservative ESA prescription. The major indication for transfusion was a low Hb rather than clinical symptoms. Initiation of HD as an inpatient was independently associated with the probability of receiving a blood transfusion. These findings require further investigation.
Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases

Introduction This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain. Methods NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing. Results In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions. Conclusion While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target.
CONDUCTIVITY IMAGING OF AN ISCHEMIC PIG HEART MODEL USING ELECTRIC PROPERTIES TOMOGRAPHY

Introduction Electric conductivity of cardiac tissue plays an important role in the function of the heart. In cardiac resynchronization therapy (CRT) it is desired to place leads of implanted devices into normally conductive tissue. Myocardial conductivity may be a useful parameter to distinguish reversible and irreversible ischemic injury [1]. Ventricular conductivity has been measured in animal studies using measurement probes but so far no non invasive tomographic method has been tested. In Electric Properties Tomography (EPT) the interaction of the transmit field used in MRI with the dielectric properties of tissue is used for non invasive and quantitative mapping of conductivity and permittivity [2]. In this work we present the application of EPT conductivity mapping in two isolated perfused pig hearts using an MR compatible set-up [3]. Conductivity values of normally perfused heart tissue were compared to values in ischemic regions after a blockade of the left anterior descending artery (LAD). Methods We performed the experiments in a system for direct coronary perfusion, in which the left and right coronary artery can be perfused independently of each other as previously described [3]. In one of the hearts the coronary artery (LAD) was occluded for 4 hours to induce severe ischemia/myocardial infarction prior to imaging on a 3T MR-scanner (Philips Healthcare, Best, Netherlands). For conductivity imaging, a volumetric SSFP image (FOV = 300 x 290 x 175mm3, resolution 2.4 x 2.4 x 5mm3, short axis slices, nonselective block RF pulse, α=25°, TR/TE = 2.6 / 1.13 ms) was employed. The SSFP sequence was gated to a window of 80ms at 500ms into the cardiac cycle. Conductivity reconstruction was performed using the phase images of the SSFP scan on a voxel by voxel basis [2]. The effect of ischemia was validated using MR perfusion imaging based on a saturation recovery gradient echo pulse sequence (TR / TE = 2.7 / 0.9 ms, α=20°, resolution 1.3 x 1.3 x 8 mm, k–t BLAST). Results / Discussion Conductivity values measured in this study are shown in Tab. 1 and the corresponding images are shown in Fig. 1. Normal values for conductivity at 128 MHz are in agreement with literature values according to [4]. Conductivity in ischemic/infarcted areas was 60% lower than in remote myocardium. A decrease of conductivity in canine two hours after LAD occlusion of up to 35% was observed elsewhere using measurement probes [5]. It is likely that the decrease in conductivity and its relation to perfusion reflects the loss of volume fraction of ion conductivity through loss of extracellular space which would include the intravascular volume [6]. Conclusions Non invasive cardiac magnetic resonance conductivity imaging is feasible in isolated perfused pig hearts. A comparison of two pig hearts showed that ischemic ventricular tissue is less conductive than healthy myocardium.
Brain MRI fiber-tracking reveals white matter alterations in hypertensive patients without damage at conventional neuroimaging

Aims Hypertension is one of the main risk factor for dementia. The subtle damage provoked by chronic high blood pressure in the brain is usually evidenced by conventional magnetic resonance imaging (MRI), in terms of white matter (WM) hyperintensities or cerebral atrophy. However, it is clear that by the time brain damage is visible, it may be too late hampering neurodegeneration. Aim of this study was to characterize a signature of early brain damage induced by hypertension, before the neurodegenerative injury manifests. Methods and results This work was conducted on hypertensive and normotensive subjects with no sign of structural damage at conventional neuroimaging and no diagnosis of dementia revealed by neuropsychological assessment. All individuals underwent cardiological clinical examination in order to define the hypertensive status and the related target organ damage. Additionally, patients were subjected to DTI-MRI scan to identify microstructural damage of WM by probabilistic fiber-tracking. To gain insights in the neurocognitive profile of patients a specific battery of tests was administered. As primary outcome of the study we aimed at finding any specific signature of fiber-tracts alterations in hypertensive patients, associated with an impairment of the related cognitive functions. Hypertensive patients showed significant alterations in three specific WM fiber-tracts: the anterior thalamic radiation, the superior longitudinal fasciculus and the forceps minor. Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those WM fiber-tracts, showing decreased performances in executive functions, processing speed, memory, and paired associative learning tasks. Conclusions Overall, WM fiber-tracking on MRI evidenced an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging. In perspective, this approach could allow identifying those patients that are in initial stages of brain damage and could benefit of therapies aimed at limiting the transition to dementia and neurodegeneration.
An investigation of the determinants of quality of life in adolescents and young adults with Down syndrome

Background Young people with Down syndrome experience varying abilities in activities of daily living, cognitive functioning, behaviour and social skills. The aim of this research was to investigate, from a carer’s perspective, the factors that influenced the quality of life of these young people. Methods Families of young people with Down syndrome (n = 197), aged 16–31 years, living in Western Australia, took part in a questionnaire study regarding young person daily functioning, family characteristics, medical background and quality of life measured by the Kidscreen 27-item scale. Kidscreen-10 total score was used as an outcome in the investigation of determinants with higher scores indicating better quality of life. Results After adjustment for confounders including carer’s mental health measured by the Depression and Anxiety Scale (DASS), global impact of illness as well as impact of mental health and bowel conditions were all negatively associated with the young person’s quality of life. Young people who had three or more friends had better quality of life than those with no friends. Scores were lower (reflecting poor quality of life) in individuals who had more behavioural problems but these relationships were attenuated after adjustment for confounders and DASS. Conclusions Overall, our findings revealed that quality of life of young people with Down syndrome was most negatively associated with burden of medical conditions, but also with lack of friendships. We were somewhat surprised to find the effect of medical problems on quality of life persisting into adolescence and adulthood where in general the burden of medical comorbidities is much less than in childhood.