Search

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Abstract Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5’-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10−16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10−3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.

Many jobs today are predominantly knowledge work. This makes organizations dependent on value created by knowledge workers (KWs). Many of the initiatives to improve and manage knowledge worker productivity (KWP) give unpredictable results depending on factors that are often hidden and unknown. It is important to find a holistic approach to improve and manage KWP that gives consistent results across many different organizations. This paper takes us a step closer towards that objective by mapping insights gained from a systematic literature review to activities in a purposeful activity model of the individual KW at work and, based on the findings, proposing a draft of a holistic KWP framework. The main components of the framework are the state of the individual KW, work done and outcome. The systematic literature review searched for papers with topics that touched on approaches, frameworks, tools, or models which aim to tackle the productivity, performance, effectiveness, efficiency, or management of KWs. Relevant concepts were extracted from each paper and categorized into groups. Twelve groups were formed of which six consisted of concepts relevant to individual KWs and their work: organizational commitment and engagement, communication and relationships, personal characteristics and development, personal knowledge management, well-being and job satisfaction and task approach.

This research attempted to find and define holistic systems that affect the productivity of the knowledge worker (KW), using the soft systems methodology (SSM). It is not enough to look at the management and improvement of knowledge worker productivity (KWP) from the viewpoint of the organization. The viewpoint of the individual KW needs to be considered as well. The KW owns the means of production; they carry their knowledge in their heads and take it with them when changing jobs. This paper proposes a conceptual framework that describes the process in which the KW uses resources to execute actions to create tangible or intangible artifacts with the intention of generating value. It was based on interpretations and inferences made from an extensive literature review using the snowballing method. This paper highlights what implications the lessons learned from the conceptual framework have on managing and improving KWP and delves deeper into four key concepts: value in knowledge work, knowledge, personal resources, and competencies.