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Background Patient navigators have been introduced across various countries to enable timely access to healthcare services and to ensure completion of diagnosis and follow-up of care. There is an increasing evidence on the the role of patient navigation for patients and healthcare systems. The aim of this study was to analyse the evidence on patient navigation interventions in ambulatory care and to evaluate their effects on individuals and health system outcomes. Methods An overview of reviews was conducted, following a prespecified protocol. All patients in ambulatory care or transitional care setting were included in this review as long as it was related to the role of patient navigators. The study analysed patient navigators covering a wide range of health professionals such as physicians, nurses, pharmacists, social workers and lay health workers or community-based workers with no or very limited training. Studies including patient-related measures and health system-related outcomes were eligible for inclusion. A rigorous search was performed in multiple data bases. After reaching a high inter-rater agreement of 0.86, title and abstract screening was independently performed. Of an initial 14,248 search results and an additional 62 articles identified through the snowballing approach, a total of 7159 hits were eligible for title/abstract screening. 679  articles were included for full-text screening. Results Eleven systematic reviews were included covering various patient navigation intervention in cancer care, disease screening, transitional care and for various chronic conditions and multimorbidity. Nine systematic reviews primarily tailored services to ethnic minorities or other disadvantaged groups. Patient navigators performed tasks such as providing education and counselling, translations, home visits, outreach, scheduling of appointments and follow-up. Eight reviews identified positive outcomes in expanding access to care, in particular for vulnerable patient groups. Two reviews on patient navigation in transitional care reported improved patient outcomes, hospital readmission rates and mixed evidence on quality of life and emergency department visits. Two reviews demonstrated improved patient outcomes for persons with various chronic conditions and multimorbidity. Conclusions Patient navigators were shown to expand access to screenings and health services for vulnerable patients or population groups with chronic conditions who tend to underuse health services.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Background Country-level data suggest large differences in the supply of health professionals among European countries. However, little is know about the regional supply of health professionals taking a cross-country comparative perspective. The aim of the study was to analyse the regional distribution of physicians, nurses and midwives in the highest and lowest density regions in Europe and examine time trends. Methods We used Eurostat data and descriptive statistics to assess the density of physicians, nurses and midwives at national and regional levels (Nomenclature of Territorial Units for Statistics (NUTS) 2 regions) for 2017 and time trends (2005–2017). To ensure cross-country comparability we applied a set of criteria (working status, availability over time, geographic availability, source). This resulted in 14 European Union (EU) countries and Switzerland being available for the physician analysis and eight countries for the nurses and midwives analysis. Density rates per population were analysed at national and NUTS 2 level, of which regions with the highest and lowest density of physicians, nurses and midwives were identified. We examined changes over time in regional distributions, using percentage change and Compound Annual Growth Rate (CAGR). Results There was a 2.4-fold difference in the physician density between the highest and lowest density countries (Austria national average: 513, Poland 241.6 per 100,000) and a 3.5-fold difference among nurses (Denmark: 1702.5, Bulgaria: 483.0). Differences by regions across Europe were higher than cross-country variations and varied up to 5.5-fold for physicians and 4.4-fold for nurses/midwives and did not improve over time. Capitals and/or major cities in all countries showed a markedly higher supply of physicians than more sparsely populated regions while the density of nurses and midwives tended to be higher in more sparsely populated areas. Over time, physician rates increased faster than density levels of nurses and midwives. Conclusions The study shows for the first time the large variation in health workforce supply at regional levels and time trends by professions across the European region. This highlights the importance for countries to routinely collect data in sub-national geographic areas to develop integrated health workforce policies for health professionals at regional levels.

Key Points Treatment of restless legs syndrome (RLS) usually involves dopamine agonists, which are approved for treatment of RLS in most countries; α-2-δ ligands, such as gabapentin enacarbil and pregabalin, are also effective In patients with RLS who have low levels of ferritin, iron supplementation should be the first-line therapy For patients with severe RLS, opioids such as oxycodone–naloxone are an option as second-line therapy where they are approved Augmentation is a major complication of long-term RLS therapy with dopaminergic agents, and is related to high doses of dopaminergics International treatment guidelines recommend weighing the benefits against the risks for each drug class when initiating treatment Combined treatment approaches are used on the basis of expert opinions, and are currently not evidenced-based Restless legs syndrome that reduces quality of life and disturbs sleep requires pharmacological intervention. In the context of current guidelines and diagnostic criteria, Claudia Trenkwalder and colleagues summarize the treatments that are currently approved and used in clinical practice, including combination therapies. They also draw on their clinical experience to discuss and advise on the management of augmentation induced by dopaminergic drugs. Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone–naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.

Adenosine deaminase 2 (ADA2) is a protein with at least two functions. It is a growth factor affecting leukocytes and endothelial cells and an enzyme that influences purine metabolism. This study shows that mutant ADA2 causes polyarteritis nodosa. Polyarteritis nodosa, first described in 1866, 1 is a systemic necrotizing vasculitis that affects medium and small muscular arteries. 2 , 3 The ensuing tissue ischemia can affect any organ, including the skin, musculoskeletal system, kidneys, gastrointestinal tract, and the cardiovascular and nervous systems. Polyarteritis nodosa is usually diagnosed in middle age or later but can appear in childhood. 2 , 4 , 5 The diagnosis remains challenging despite classification criteria for adults 6 and children, 7 because polyarteritis nodosa frequently presents with nonspecific constitutional symptoms, and organ involvement and disease severity are highly varied. Polyarteritis nodosa is most often primary, but in adults it may be associated . . .

MEIS1 and MEIS2 encode highly conserved homeodomain transcription factors crucial for developmental processes in a wide range of tissues, including the brain. They can execute redundant functions when co-expressed in the same cell types, but their roles during early stages of neural differentiation have not been systematically compared. By separate knockout and overexpression of MEIS1 and MEIS2 in human neural stem cells, we find they control specific sets of target genes, associated with distinct biological processes. Integration of DNA binding sites with differential transcriptomics implicates MEIS1 to co-regulate gene expression by interaction with transcription factors of the SOX and FOX families. MEIS1 harbors the strongest risk factor for restless legs syndrome (RLS). Our data suggest that MEIS1 can directly regulate the RLS-associated genes NTNG1 , MDGA1 and DACH1 , constituting new approaches to study the elusive pathomechanism or RLS.

Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone–naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment. This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23). We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone–naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31·6 (SD 4·5); mean change after 12 weeks was −16·5 (SD 11·3) in the prolonged release oxycodone–naloxone group and −9·4 (SD 10·9) in the placebo group (mean difference between groups at 12 weeks 8·15, 95% CI 5·46–10·85; p<0·0001). After the extension phase, mean sum score was 9·7 (SD 7·8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone–naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone–naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain). Prolonged release oxycodone–naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs. Mundipharma Research.

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin ( GRN ) and the triggering receptor expressed on myeloid cells 2 ( TREM2 ). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn −/− mice and compared their transcriptomes to those of Trem2 −/− mice . Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn −/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐ d ‐glucose)‐μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction. Synopsis Microglia from Grn −/− & Trem2 −/− mice display opposite molecular signatures. While microglia are either locked in a hyperactivated or homeostatic state, Grn −/− & Trem2 −/− mice both show reduced glucose metabolism, suggesting that opposite microglial phenotypes result in similar brain dysfunction. First demonstration that microglia from both extremes of their functional stages cause brain wide dysfunctions. This study indicates that the therapeutic window for microglial modulation is rather narrow and care must be taken to balance microglial activity. Graphical Abstract Microglia from Grn −/− & Trem2 −/− mice display opposite molecular signatures. While microglia are either locked in a hyperactivated or homeostatic state, Grn −/− & Trem2 −/− mice both show reduced glucose metabolism, suggesting that opposite microglial phenotypes result in similar brain dysfunction.

Background Hypertension (HTN) has been linked to changes in DNA methylation. However, longitudinal epigenome-wide analyses are still limited. Methods We analyzed data from the KORA F4 and FF4 studies, conducted approximately 7 years apart. The dataset included 2614 participants, each with DNA methylation measured at least once. Leucocyte DNA methylation was profiled using the Illumina 450 k and EPIC arrays. Linear mixed-effects models were employed to identify associations between methylation sites and HTN status, systolic (SBP) and diastolic blood pressure (DBP). Interaction terms with follow-up time captured longitudinal methylation trajectories. We further examined CpG sites related to reversed, persistent, or progressive HTN and assessed their correlations with gene expression. Results One CpG site was associated with SBP and four with DBP, all representing novel loci, including RILP (cg08625564) and SVIL (cg15298791). Differential annual methylation changes were observed for 2, 23, and 12 CpG sites by HTN status, SBP, and DBP, respectively, highlighting genes such as RHPN2 , CLDND1 , ZNF69 , and FKBP1B . Twenty CpG sites were associated with persistent HTN, including PLCB2 and MPPE1 . In whole blood, 22 significant CpG–transcript pairs were detected, involving 14 CpG sites and 19 gene transcripts. Conclusions This longitudinal epigenome-wide study identified novel CpG sites associated with blood pressure and persistent HTN. We observed differential DNA methylation trajectories over time linked to HTN, SBP, and DBP, with several changes correlating with gene expression, suggesting functional relevance. These findings underscore the dynamic role of DNA methylation in blood pressure regulation and provide new insights into epigenetic mechanisms of HTN. Graphical Abstract