Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Beyond the Pill : Moving from products to value-added services in the pharmaceutical industry

Background: The pharmaceutical industry is experiencing a period of far-reaching changes. Increased competitive pressures, patent expiries and payers’ outcome focus pose high challenges to the industry. Offering value-added services to a product as a measure to improve health outcomes and to achieve competitive advantage is currently being discussed and implemented to face these challenges. Objective: This paper’s aim is to analyse to what extend service strategies “beyond the pill” are and will be integrated into the pharmaceutical business model, and to assess if industry really is moving from a product-only focus to value-added services. The scope of the study is global and concentrates on manufacturing companies of branded pharmaceuticals. Method: The research covers a literature research on strategies “beyond the pill” covering potentials for value-added services, the current service landscape and challenges to service implementation. The literature research is complemented by a survey on 56 experts working for the pharmaceutical industry and their perceptions on the current situation of service strategies within the industry. Results: Both the literature research and the survey revealed that service strategies will gain importance. However, there are still multiple challenges to overcome. Legal restrictions, difficulties in measuring return on investments, conservative business philosophies and mistrust towards the pharmaceutical industry are factors slowing down the advance of service strategies

Symposium Celebrating Women Surgeons Around the World

Introduction We must thank Dr. Sanziana Roman for organizing this symposium about women in surgery. Powerful testimonials from women surgeons, from Europe to the United States, from Africa to Australia and Asia. Each of them is different, as it reflects the culture of the place where their career took place. However, they all have in common the struggle to establish themselves in the surgical profession, traditionally a male-dominated field. Over the last two decades, the situation has clearly improved. Today in most medical schools about 50% of the students are women, and a similar percentage is present in many surgical residency programs. Twenty-one Departments of Surgery in the United States are led by women, a major change as compared to only 5 years ago. Much more must be done to establish a work environment where women are as welcomed and respected as men; where they are accepted as surgeons, and not as women surgeons, treasuring the contribution they can give. We do hope that..

ePresciption as an Element of Interprofessional Pathways for continuous medication safety management (eRIKA) – a Living Lab as an Iterative Co-Design Process for a Participative Intervention Development

Physicians and pharmacies often do not have access to relevant and comprehensive information needed for safe drug prescribing and comprehensive pharmaceutical consultations [1]. Medication errors based on information deficits are frequently observed in routine care, which leads to patient harm [2–8]. About half of adverse drug reactions are traced back to medication errors and inadequate prescriptions and are thus preventable [5, 9–14]. This is often caused by physicians’ lack of knowledge of prescription standards [15–17]. Shortcomings in communication within the health sector, including between physicians and pharmacists, are common factors causing adverse drug events [18]. Insufficient information for patients about their medication further favours errors in drug use. Several digital interventions for safer drug prescription, administration and management have been proposed, developed and tested [19, 20]. Despite the increasing availability of digital interventions, few show health improvements or sustained use by patients or providers. This is often explained by a disconnect between users and developers, who do not take users’ perspectives and needs into consideration [21]. Usability is a key determinant for implementation and sustained use of new (digital) interventions [22]. Through (1) early engagement of target users and (2) user testing, user-centered designs can help overcome implementation challenges and user dissatisfaction [22] and improve the translation of evidence-based interventions from health research into routine care [23]. The Living Lab, a collaborative and iterative process for intervention design, is part of a larger interprofessional project with a mixed-methods design funded by the Innovation Fund of the Federal Joint Committee. The aim of the digital eRIKA intervention itself is to facilitate communication on pharmacotherapy information between physicians, pharmacists and hospitals alongside the introduction of the German ePrescription to ensure safer pharmacotherapy for patients with polypharmacy. The intervention will be implemented and tested in the regions Saarland, Westfalen-Lippe and Berlin-Brandenburg. Characteristics of eRIKA will be (1) the use of the ePrescription in accordance with the legal framework, (2) the use of dispensing data to enable a continuous, comprehensive and up-to-date electronic medication plan (BMP), (3) central storage of patients medication data through the BMP and electronic patient records, which is usable and editable for physicians and pharmacists, (4) electronically supported assessments of each prescription in the current medication plan, (5) optimized pharmaceutical consultation when filling a prescription through the availability of the complete medication plan and patient individual factors, (6) easier communication between physicians and pharmacists through KIM (Kommunikation im Medizinwesen – communication in medicine), the communication service provided for medical practices, (7) batch-specific traceability of drugs to the patient, (8) drug safety assessments at the point of prescription

Endophilin marks and controls a clathrin-independent endocytic pathway

Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition. This pathway is prominent at the leading edges of cells where phosphatidylinositol-3,4-bisphosphate—produced by the dephosphorylation of phosphatidylinositol-3,4,5-triphosphate by SHIP1 and SHIP2—recruits lamellipodin, which in turn engages endophilin. This pathway mediates the ligand-triggered uptake of several G-protein-coupled receptors such as α2a- and β1-adrenergic, dopaminergic D3 and D4 receptors and muscarinic acetylcholine receptor 4, the receptor tyrosine kinases EGFR, HGFR, VEGFR, PDGFR, NGFR and IGF1R, as well as interleukin-2 receptor. We call this new endocytic route fast endophilin-mediated endocytosis (FEME)

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele