Preventive health risk appraisal for older people and impact on GPs' patient management: a prospective study

Background. Health risk appraisals (HRAs) are recommended for detection of potentially modifiable risk factors for health status decline of older people. Little is known how family physicians manage detected risk factors. Objective. We evaluated (i) if risk factors in one or more of five predefined domains were detected in a primary care-based HRA and (ii) how often these findings had an impact on the further management of patients. Methods. We performed a prospective observational study in a rural community in Austria and included persons (age ≥ 70 years) living at home. We applied the standardized assessment for elderly people in primary care (STEP) instrument and evaluated risk factors for status decline assessing five domains (cognitive function, depression, urinary incontinence, hearing impairment and mobility/falls). Results. Two hundred and sixty-four persons participated and the HRA revealed a wide range of risk factors for health status decline [from 4.5% (12/264) in the depression domain up to 31% (81/264) for mobility/falls and 41% (107/264) in the cognitive domain]. The findings had an impact on the further management in four domains: hearing impairment (100% of findings with impact), mobility/falls (93%), depression (83%) and urinary incontinence (65%). In contrast, abnormal cognitive findings lead to action only in every fifth participant (18%; 19/107). Conclusion. In contrast to other domains, family physicians are hesitant to act upon abnormal findings of cognitive testing. Additional knowledge is needed to clarify the value of abnormal cognitive findings for management of patients and support of their carer

Epidemiology and costs of multiple sclerosis in Switzerland : an analysis of health-care claims data, 2011–2015

Background: Medical therapy for multiple sclerosis (MS) is expensive. Quantifying the burden of MS is fundamental for health-care planning and the allocation of resources for the management of MS. This study provides current national estimates of prevalence, incidence, mortality, and costs of MS in Switzerland using claims data between 2011 and 2015. Methods: We analyzed health insurance claims of adult persons enrolled with a large health insurance group covering about 13% of the Swiss population between 2011 and 2015. The identification of patients with MS was based on prescription data of MS-specific medication using the Anatomical Therapeutic Chemical Classification system as proxy for clinical diagnosis. We estimated prevalence, mortality, and costs of basic health insurance between 2011 and 2015. Furthermore, incidence of MS was calculated for 2015. All results were weighted with census data to achieve an extrapolation to the Swiss general population level. Cost of illness was estimated as direct medical cost from the perspective of a Swiss health insurance using multivariate linear regression analysis. Results: Of the 943,639 subjects in the year 2015, 1,606 were identified as MS patients resulting in a prevalence of 190 per 100,000 (95% CI: 180-190 per 100,000). Incidence was 16 per 100,000 (95% CI: 13-19 per 100,000). According to regression analysis, the total cost of illness for basic mandatory health insurance was 26,710 Swiss Francs (CHF) (95% CI: 26,100-27,300) per person per year with the cost of medication being almost identical 26,960 CHF (95% CI: 26,170-27,800). Conclusions: MS affects 10,000–15,000 persons in Switzerland, and the prevalence has increased over the last 22 years. These persons have high need and demand for health care. High costs are primarily due to expenses for medication. Given the imbalance of MS medication therapy from the perspective of basic health insurance on the disposable resources, it is crucial to increase transparency related to the volume, type, and allocation of expenses

Macrophage Polarization is Deregulated in Haemophilia

Macrophages make important contributions to inflammation and wound healing. We show here that macrophage polarization is deregulated in haemophilia in response to macrophage colony-stimulating factor (M-CSF) and partially in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). As a result, haemophilia macrophages exhibit a specific impairment of M-CSF-mediated functions involved in wound healing such as clot invasion and phagocytosis. Haemophilia monocytes express reduced amounts of the receptors for M-CSF and GM-CSF, which correlates with a failure to express tumour necrosis factor α (TNFα) and CD163 in M-CSF-treated haemophilia macrophages and reduced expression of TNFα and CD206 after treatment with GM-CSF. Protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding haemophilia monocytes in clotted plasma suggesting that a functioning coagulation system has positive effects on macrophage M2 polarization. Mimicking the functional deficits of haemophilia macrophages in normal macrophages was possible by adding leptin, which we found to be elevated in the blood of haemophilia patients, to a monocyte cell line. The increase of leptin occurred in conjunction with C-reactive protein in a body mass index-controlled cohort suggesting that haemophilia patients harbour chronic low-grade inflammation. Together, our data indicate that impaired clotting in haemophilia patients leads to increased inflammation and a deregulation in macrophage differentiation, which may explain the commonly observed deficits in wound healing and tissue regeneration

Preventive health risk appraisal for older people and impact on GPs' patient management : a prospective study

Background: Health risk appraisals (HRAs) are recommended for detection of potentially modifiable risk factors for health status decline of older people. Little is known how family physicians manage detected risk factors. Objective: We evaluated (i) if risk factors in one or more of five predefined domains were detected in a primary care-based HRA and (ii) how often these findings had an impact on the further management of patients. Methods: We performed a prospective observational study in a rural community in Austria and included persons (age ≥ 70 years) living at home. We applied the standardized assessment for elderly people in primary care (STEP) instrument and evaluated risk factors for status decline assessing five domains (cognitive function, depression, urinary incontinence, hearing impairment and mobility/falls). Results: Two hundred and sixty-four persons participated and the HRA revealed a wide range of risk factors for health status decline [from 4.5% (12/264) in the depression domain up to 31% (81/264) for mobility/falls and 41% (107/264) in the cognitive domain]. The findings had an impact on the further management in four domains: hearing impairment (100% of findings with impact), mobility/falls (93%), depression (83%) and urinary incontinence (65%). In contrast, abnormal cognitive findings lead to action only in every fifth participant (18%; 19/107). Conclusion: In contrast to other domains, family physicians are hesitant to act upon abnormal findings of cognitive testing. Additional knowledge is needed to clarify the value of abnormal cognitive findings for management of patients and support of their carers

Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders.

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversionsretrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 1

recommendations by the Conect4Children expert advice group

Funding Information: Competing interests: A.V.R. has received Speaker fees/Consultant for Abbvie, Novartis, UCB, SOBI, Eli Lilly and Roche. N.M. reports grants outside the submitted work in the last five years from the Medical Research Council, National Institute of Health Research, March of Dimes, British Heart Foundation, HCA international, Health Data Research UK, Shire Pharmaceuticals, Chiesi Pharmaceuticals, Prolacta Life Sciences, and Westminster Children’s Research Fund; N.M. is a member of the Nestle Scientific Advisory Board and accepts no personal remuneration for this role. N.M. reports travel and accommodation reimbursements from Chiesi, Nestle and Shire. N.M. is a member of C4C, International Neonatal Collaboration (INC), UK National Research Ethics Advisory Service and MHRA advisory groups and/or working parties. S.W. has received compensation as a member of the scientific advisory board of AM Pharma, Novartis and Khondrion and receives research funding from IMI2 for the Conect4children project. B.A. has worked for GlaxoSmithKline between October 2006 and September 2009 and holds company shares. Between October 2009 and May 2015, she has worked for Novartis. M.S. has recieved research grant and honoraria for meetings and Advisory Boards from Alexion, Sanofi/Genzyme, Takeda, CHIESI, Ultragenix, Orchard, Orphazyme. P.I. is a permanent employee of Bayer AG, Germany. M.V. has received compensation for Advisory boards or Steering committes from Roche, Novartis, Achillion, Apellis, Retrophin/Travere, Alexion pharmaceuticals. C.M. has been a consultant to or has received honoraria from Janssen, Angelini, Servier, Nuvelution, Otsuka, Lundbeck, Pfizer, Neuraxpharm and Esteve outside the submitted work. She declares conflicts of interest unrelated to the present work. M.C. had advisory roles for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, and Roche in the last 2 years (outside the topic of the submitted work, for oncology drugs). M.J. has received research grants from Shire and has been engaged as a speaker or consultant by Shire, Ginsana, PCM Scientific Evolan, and New Nordic, all unrelated to the present work. P.S. has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, and has received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. E.R. has received speaker fees and participated at advisory boards for Eisai and has received research funding by GW Pharmaceuticals, Pfizer, Italian Ministry of Health (MoH) and the Italian Medicine Agency (AIFA). This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). M.A.R. is a member of the c4c Ethics Expert Group and received compensation for ethical consulting activities from Bayer AG Wallace Crandall is employee of Eli Lilly and Co. P.C. is an employee of UCB, and owns stock in the company. She was previously an employee of GSK and owns stock in the company. N.R. has received honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB. The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions from the following industries in the last 3 years: Bristol Myers and Squibb, Eli-Lilly, F Hoffmann-La Roche, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties. M.L. receives/has received consultation fees from CSL Behring, Novartis, Roche and Octopharma, travel grants from Merck Serono, and been awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer. All other authors have no disclosures. Funding Information: Conect4children has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777389. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The views expressed in this article are the personal views of the author(s) and should not be interpreted as made on behalf of, or reflecting the position of, the regulatory agency/agencies or organisations with which the author(s) is/are employed/affiliated . Publisher Copyright: © 2021, The Author(s).Background: The COVID-19 pandemic has had a devastating impact on multiple aspects of healthcare, but has also triggered new ways of working, stimulated novel approaches in clinical research and reinforced the value of previous innovations. Conect4children (c4c, www.conect4children.org) is a large collaborative European network to facilitate the development of new medicines for paediatric populations, and is made up of 35 academic and 10 industry partners from 20 European countries, more than 50 third parties, and around 500 affiliated partners. Methods: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equity. Findings: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equityWe provide examples of research innovation, and follow this with recommendations to improve the efficiency of future trials, drawing on industry perspectives, regulatory considerations, infrastructure requirements and parent–patient–public involvement. We end with a comment on progress made towards greater international harmonisation of paediatric research and how lessons learned from COVID-19 studies might assist in further improvements in this important area.publishersversionepub_ahead_of_prin

Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms, whereas inflammation allegedly plays no role in AMN. How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. To gain insights into these questions, we undertook a transcriptomic approach followed by a functional-enrichment analysis in spinal cords of the animal model of AMN, the Abcd1− null mice, and in normal-appearing white matter of cAMN and cALD patients. We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation, adipocytokine and insulin signaling pathways, and protein synthesis. Functional validation by quantitative polymerase chain reaction, western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase, being VLCFA in excess a causal, upstream trigger promoting the altered signature. We conclude that X-ALD is, in all its variants, a metabolic/inflammatory syndrome, which may offer new targets in X-ALD therapeutics