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

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

Kompetenznetz Schizophrenie. Optimierung der Schizophreniebehandlung in der Allgemeinarztpraxis Schlussbericht

SIGLEAvailable from TIB Hannover: F03B640+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung und Forschung, Berlin (Germany)DEGerman

Fertilitaetsstoerungen. Verbesserung der psychosozialen und medizinischen Betreuung von Kinderwunschpatienten in der primaeraerztlichen Versorgung Abschlussbericht

SIGLEAvailable from TIB Hannover: F01B308 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Evaluating an educational intervention to inprove the treatment of asthma in four European countries

New British guidelines on the treatment of asthma (9) advocate starting with a higher dose of inhaled corticosteroids in newly detected asthma patients. We investigated whether initiating inhaled steroid treatment with a higher dose is clinically more effective than a lower dose in steroid naive patients with asthma. The study had a 13-wk randomized, double-blind, parallel design: 1-mo treatment with 400 microg budesonide twice a day, or 100 microg budesonide twice a day by dry powder inhaler, and follow-up treatment period of 2 mo with 200 microg budesonide once daily for all patients. Forty patients started with 400 microg budesonide twice daily, 44 with 100 microg budesonide twice daily. Mean age was 32 yr, baseline FEV1 value 84% predicted, reversibility 9% from baseline, and mean bronchodilator use 1.6 inhalations/d in the run-in period. After 4 wk of treatment with 400 microg and 100 microg budesonide twice daily mean morning peak expiratory flow (PEF) increased 27 L/min (SD 50), and 38 L/ min (SD 53), respectively (p = 0.30); mean symptom score improved from 1.1 to 0.6 and from 1.1 to 0.5. These effects were maintained in the 2 mo follow-up. This study suggests that starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma.

Quality circles to improve prescribing patterns in primary medical care: what is their actual impact?

Contains fulltext : 57952.pdf (publisher's version ) (Closed access)RATIONALE, AIMS AND OBJECTIVES: Quality circles comprise small group sessions of doctors and written feedback on their individual practice patterns. Although 50% of German primary care doctors participate in quality circles, their effectiveness has hardly been evaluated in Germany. This study determined the impact of a large-scale programme of quality circles on quality and costs of prescribing. METHOD: A controlled before-after study was performed, in which primary care doctors were allocated to a quality circles group or a control group. Subjects were 100,000 patients in 1996 and in 1998, who had visited one of 177 doctors in the 3 month registration periods in one region in Germany. The intervention comprised a quality circles programme, comprising 11 sessions and repeated feedback on prescribing. Main outcome measures were proportion of patients who received a prescription, mean prescription costs per patient and proportion of generic prescriptions. RESULTS: The absolute numbers of prescriptions decreased in both groups, but the mean prescription costs per patient increased. The quality circles reduced the proportion of patients who received a prescription (OR = 0.86) and the mean prescription costs per patient (B = -3.99 euro), while it increased the proportion of generic drugs (OR = 1.10). The intervention had intended effects on four of the 15 secondary indicators. CONCLUSIONS: Large-scale application of quality circles had intended effects on prescribing decisions in primary care in Germany. The effects found in this study may reflect better what improvements can be achieved than randomized trials of similar interventions

Implementation of a guideline for low back pain management in primary care: A cost-effectiveness analysis.

Study Design. Cost-effectiveness analysis alongside a cluster randomized controlled trial. Objective. To study the cost-effectiveness of 2 low back pain guideline implementation (GI) strategies. Summary of Background Data. Several evidence-based guidelines on management of low back pain have been published. However, there is still no consensus on the effective implementation strategy. Especially studies on the economic impact of different implementation strategies are lacking. Methods. This analysis was performed alongside a cluster randomized controlled trial on the effectiveness of 2 GI strategies (physician education alone [GI] or physician education in combination with motivational counseling [MC] by practice nurses)-both compared with the postal dissemination of the guideline (control group, C). Sociodemographic data, pain characteristics, and cost data were collected by interview at baseline and after 6 and 12 months. low back pain-related health care costs were valued for 2004 from the societal perspective. Results. For the cost analysis, 1322 patients from 126 general practices were included. Both interventions showed lower direct and indirect costs as well as better patient outcomes during follow-up compared with controls. In addition, both intervention arms showed superiority of cost-effectiveness to C. The effects attenuated when adjusting for differences of health care utilization prior to patient recruitment and for clustering of data. Conclusion. Trends in cost-effectiveness are visible but need to be confirmed in future studies. Researchers performing cost-evaluation studies should test for baseline imbalances of health care utilization data instead of judging on the randomization success by reviewing non-cost parameters like clinical data alone