Search

Western liberalism is based on two different humanistic traditions: First, the biblical tradition of the Abrahamic religions, according to which man was created in the image of God; and, second, the tradition that developed in the age of Enlightenment, which claims man’s absolute independence of any heteronomous or transcendental being and views the very existence as a goal in and of itself. Each one of these two traditions restricts the autonomy of the individual in different ways, thus influencing the constitutional structure one of whose principal functions is to safeguard the autonomy of the citizens. This article deals with the theological value of autonomy. It analyzes the tension between the humanistic-anthropocentric worldview, which sanctifies human freedom, and the humanistic-theocentric way of thinking, which sees God as the source of all norms and holds that the freedom of man is limited by the divine imperative. Subsequently, the article presents three different models of understanding the relations between the will of God and the will of man, through an analysis of the exegesis of three Jewish thinkers on the stories of man’s creation in the image of God and the sin of the Primordial Man. These models represent three attitudes towards the theological value of autonomy. After having presented the different models, I shall compare them to each other and explicate the conceptual differences between them. To conclude, I shall further assess the contribution of these models to contemporary discourse on autonomy and liberty.

I study the impact of transportation on health in the rural United States, 1820–1847. Measuring health by average stature, I find that greater transportation linkage, as measured by market access, in a cohort’s county-year of birth had an adverse impact on its health. A one-standard-deviation increase in market access reduced average stature by 0.14 inches, and rising market access over the study period can explain 37 percent of the contemporaneous decline in average stature, known as theAntebellum Puzzle. I find evidence that transportation affected health by increasing population density, leading to a worse epidemiological environment.

Attempts to expand ex vivo the numbers of human hematopoietic stem cells (HSCs) without compromising their marrow repopulating capacity and their ability to establish multilineage hematopoiesis has been the subject of intense investigation. Although most such efforts have focused on cord blood HSCs, few have been applied to adult HSCs, a more clinically relevant HSC source for gene modification. To date, the strategies that have been used to expand adult HSCs have resulted in modest effects or HSCs with lineage bias and a limited ability to generate T cells in vivo. We previously reported that culturing umbilical cord blood CD34+ cells in serum‐free media supplemented with valproic acid (VPA), a histone deacetylase inhibitor, and a combination of cytokines led to the expansion of the numbers of fully functional HSCs. In the present study, we used this same approach to expand the numbers of adult human CD34+ cells isolated from mobilized peripheral blood and bone marrow. This approach resulted in a significant increase in the numbers of phenotypically defined HSCs (CD34+CD45RA‐CD90+D49f+). Cells incubated with VPA also exhibited increased aldehyde dehydrogenase activity and decreased mitochondrial membrane potential, each functional markers of HSCs. Grafts harvested from VPA‐treated cultures were able to engraft in immune‐deficient mice and, importantly, to generate cellular progeny belonging to each hematopoietic lineage in similar proportion to that observed with unmanipulated CD34+ cells. These data support the utility of VPA‐mediated ex vivo HSC expansion for gene modification of adult HSCs., Valproic acid (VPA)‐mediated ex vivo expansion of adult bone marrow and mobilized peripheral blood CD34+ cells resulted in a cellular product characterized by high viability, enrichment with CD34+CD45RA‐CD90+ cells, increased aldehyde dehydrogenase (ALDH) activity, robust multipotent clonogenic potential, and decreased mitochondrial potential. VPA‐expanded grafts were able to establish unbiased multilineage human hematopoietic‐cell chimerism in NSG mice at 16 weeks post‐transplantation.

The exhaustion of natural energy and oil reserves has initiated the concept of renewable energy systems (RESs). This has expanded the vision of energy sector towards a diversified power grid while introducing the distributed energy resources (DERs) and distributed generation (DG). Though, this diversification is achieved by adding new energy generation sources and a two-way power flow, it opens the channel of production and trading with alternating current (AC) and direct current (DC) energy formats. But DC-based energy, due to its sporadic nature, can be further stored easily by energy storage devices. However, in recent years, a compelling need has arisen to understand the communication systems in distributed generation (DG) for better performance management, control and parallel power transfer. In this article, a bibliographic review on communication systems in distributed generations (DGs) is provided. The study identifies various communication technologies, standards, and protocols used in AC and DC-based DGs. Moreover, it contains the classification of different frameworks and methods involved. The methodology of different approaches and their likely combination are discussed for different types of communication networks. This study also represents useful information for readers, thereby demonstrate the complete life-cycle of digital data in sensors/actuators, transmitter, receiver, filter, decoder for control of DG elements and identifies future challenges as well. A comprehensive list of publications to date are compiled to provide a complete picture of different developments in this area.

Purpose: AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL. Experimental Design: Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313). Results: Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5–9.5) months, all 4 patients maintained their responses. Conclusions: BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL.

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe GBA1 variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5–16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous GBA1 carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT–SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT–ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD.

Additional file 1. Patient reported outcome measure (rmGD1-PROM).

Punishment is often performed through judicial texts. Narrative criminology scholarship, however, has paid little attention to how criminalised people engage with these texts when constructing their self-narratives. To fill this gap, based on qualitative findings from formerly incarcerated people in Israel, this paper aimed to theorise their engagement with their sentencing remarks (SR). We found that they experienced their SR as text that held communicative, transformative and physical dimensions. The findings showed that SR impacted criminalised persons by individualising the penal dialogue, transforming their identity, and serving as objects for performing rituals during their imprisonment and upon release. The findings contribute to an understanding of the connection between judicial work and incarcerated people's desistance and identity-making processes through the textual bridge of SR.

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5–26) years and 30 (30–60) U/kg/month, respectively. Low FF scores (

Patients with Gaucher disease (GD) have been shown previously to carry an increased risk for cancer, most commonly multiple myeloma (MM). It is currently unknown whether treatment for GD has an effect on the prevention or amelioration of MM. We present the case of a 41-year-old patient simultaneously diagnosed with GD and smouldering MM. Enzyme replacement therapy with Velaglucerase-alfa significantly improved myeloma indices.

Lysosomes have a critical role in maintaining normal cellular homeostasis mediated by their involvement in secretion, plasma membrane repair, cell signaling and energy metabolism. Lysosomal storage disorders (LSDs) are a group of approximately 50 rare disorders caused by lysosomal dysfunction that occur due to mutations in a gene of a lysosomal protein. Gaucher disease (GD), an autosomal recessive disorder and one of the most common LSDs, is caused by the deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), due to biallelic mutations in the GBA1 gene. Reduced GCase activity leads to the accumulation of glucosylceramide (GlcCer), which is deacylated by lysosomal acid ceramidase to a toxic metabolite, glucosylshpingosine (GlcSph). Most GBA1 variants are recognized as misfolded in the ER, where the retention for refolding attempts initiates stress and activates the stress response known as the Unfolded Protein Response (UPR). The distinct clinical subtypes of GD are based on whether there is primary involvement of the central nervous system. Type 1 GD (GD1) is the nonneuropathic type, however, the recent recognition of the association of GD with the development of parkinsonism defies this classification. Patients with GD1 and carriers of GBA1 mutations are at risk for the development of parkinsonian manifestations. Parkinson disease (PD), the second most prevalent neurodegenerative disease, culminates in a movement disorder with the premature death of the patients. In PD and related disorders, collectively called synucleinopathies, the hallmark pathology is α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites and the death of dopaminergic neurons. While PD is mostly sporadic, in ∼5-10% of cases, the disease results from pathogenic variants in a growing number of genes. The most common genetic cause of PD is mutations in GBA1. Two mechanisms have been proposed for this link: (A) a "gain of function" mechanism, in which mutant GCase (protein) contributes to aggregate formation and to the development of PD, and the (B) "haploinsufficiency" ("loss of function") model, suggesting that one normal GBA1 allele is insufficient to carry adequate GCase activity and functional deficiency of GCase impedes α-synuclein metabolism. Lysosomal dysfunction, compromised autophagy and mitophagy further enhance the accumulation of α-synuclein, which results in the development of PD pathology. The present review will elaborate on the biology of GD, its association with PD and related disorders, and discuss the possible mechanisms underlying this association.