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  • 1
    Online Resource
    Online Resource
    Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
    American Medical Association (AMA) ; 2022
    In:  JAMA Neurology Vol. 79, No. 10 ( 2022-10-01), p. 975-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 79, No. 10 ( 2022-10-01), p. 975-
    Abstract: National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. Design, Setting, and Participants This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. Exposures Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T−, A−T+, A−T−). Presence (+) or absence (−) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. Results Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2022.2379
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    An Innovative Telemedical Network to Improve Infectious Disease Management in Critically Ill Patients and Outpatients (TELnet@NRW): Stepped-Wedge Cluster Randomized Controlled Trial
    JMIR Publications Inc. ; 2022
    In:  Journal of Medical Internet Research Vol. 24, No. 3 ( 2022-3-2), p. e34098-
    Details
    In: Journal of Medical Internet Research, JMIR Publications Inc., Vol. 24, No. 3 ( 2022-3-2), p. e34098-
    Abstract: Evidence-based infectious disease and intensive care management is more relevant than ever. Medical expertise in the two disciplines is often geographically limited to university institutions. In addition, the interconnection between inpatient and outpatient care is often insufficient (eg, no shared electronic health record and no digital transfer of patient findings). Objective This study aims to establish and evaluate a telemedical inpatient-outpatient network based on expert teleconsultations to increase treatment quality in intensive care medicine and infectious diseases. Methods We performed a multicenter, stepped-wedge cluster randomized trial (February 2017 to January 2020) to establish a telemedicine inpatient-outpatient network among university hospitals, hospitals, and outpatient physicians in North Rhine-Westphalia, Germany. Patients aged ≥18 years in the intensive care unit or consulting with a physician in the outpatient setting were eligible. We provided expert knowledge from intensivists and infectious disease specialists through advanced training courses and expert teleconsultations with 24/7/365 availability on demand respectively once per week to enhance treatment quality. The primary outcome was adherence to the 10 Choosing Wisely recommendations for infectious disease management. Guideline adherence was analyzed using binary logistic regression models. Results Overall, 159,424 patients (10,585 inpatients and 148,839 outpatients) from 17 hospitals and 103 outpatient physicians were included. There was a significant increase in guideline adherence in the management of Staphylococcus aureus infections (odds ratio [OR] 4.00, 95% CI 1.83-9.20; P 〈 .001) and in sepsis management in critically ill patients (OR 6.82, 95% CI 1.27-56.61; P=.04). There was a statistically nonsignificant decrease in sepsis-related mortality from 29% (19/66) in the control group to 23.8% (50/210) in the intervention group. Furthermore, the extension of treatment with prophylactic antibiotics after surgery was significantly less likely (OR 9.37, 95% CI 1.52-111.47; P=.04). Patients treated by outpatient physicians, who were regularly participating in expert teleconsultations, were also more likely to be treated according to guideline recommendations regarding antibiotic therapy for uncomplicated upper respiratory tract infections (OR 1.34, 95% CI 1.16-1.56; P 〈 .001) and asymptomatic bacteriuria (OR 9.31, 95% CI 3.79-25.94; P 〈 .001). For the other recommendations, we found no significant effects, or we had too few observations to generate models. The key limitations of our study include selection effects due to the applied on-site triage of patients as well as the limited possibilities to control for secular effects. Conclusions Telemedicine facilitates a direct round-the-clock interaction over broad distances between intensivists or infectious disease experts and physicians who care for patients in hospitals without ready access to these experts. Expert teleconsultations increase guideline adherence and treatment quality in infectious disease and intensive care management, creating added value for critically ill patients. Trial Registration ClinicalTrials.gov NCT03137589; https://clinicaltrials.gov/ct2/show/NCT03137589
    Type of Medium: Online Resource
    ISSN: 1438-8871
    URL: Article
    DOI: 10.2196/34098
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2022
    detail.hit.zdb_id: 2028830-X
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  • 3
    Online Resource
    Online Resource
    Using common genetic variants to find drugs for common epilepsies
    Oxford University Press (OUP) ; 2021
    In:  Brain Communications Vol. 3, No. 4 ( 2021-10-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 3, No. 4 ( 2021-10-01)
    Abstract: Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs’ activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs’ effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins’ dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcab287
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3020013-1
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  • 4
    Online Resource
    Online Resource
    GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
    Springer Science and Business Media LLC ; 2023
    In:  Nature Genetics Vol. 55, No. 9 ( 2023-09), p. 1471-1482
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 55, No. 9 ( 2023-09), p. 1471-1482
    Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/s41588-023-01485-w
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    5th International Symposium on Focused Ultrasound : North Bethesda, MD, USA. 28 August- 1 September 2016
    Springer Science and Business Media LLC ; 2016
    In:  Journal of Therapeutic Ultrasound Vol. 4, No. S1 ( 2016-11)
    Details
    In: Journal of Therapeutic Ultrasound, Springer Science and Business Media LLC, Vol. 4, No. S1 ( 2016-11)
    Type of Medium: Online Resource
    ISSN: 2050-5736
    URL: Article
    DOI: 10.1186/s40349-016-0076-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2714301-6
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  • 6
    Online Resource
    Online Resource
    Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
    Springer Science and Business Media LLC ; 2018
    In:  Nature Communications Vol. 9, No. 1 ( 2018-12-10)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-12-10)
    Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-018-07524-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2553671-0
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  • 7
    Online Resource
    Online Resource
    Distinct gene-set burden patterns underlie common generalized and focal epilepsies
    Elsevier BV ; 2021
    In:  eBioMedicine Vol. 72 ( 2021-10), p. 103588-
    Details
    In: eBioMedicine, Elsevier BV, Vol. 72 ( 2021-10), p. 103588-
    Type of Medium: Online Resource
    ISSN: 2352-3964
    URL: Article
    DOI: 10.1016/j.ebiom.2021.103588
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2799017-5
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  • 8
    Online Resource
    Online Resource
    Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 7 ( 2020-07-01), p. 2106-2118
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 7 ( 2020-07-01), p. 2106-2118
    Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa171
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    FemtoSpeX: a versatile optical pump–soft X-ray probe facility with 100 fs X-ray pulses of variable polarization
    International Union of Crystallography (IUCr) ; 2014
    In:  Journal of Synchrotron Radiation Vol. 21, No. 5 ( 2014-09-01), p. 1090-1104
    Details
    In: Journal of Synchrotron Radiation, International Union of Crystallography (IUCr), Vol. 21, No. 5 ( 2014-09-01), p. 1090-1104
    Abstract: Here the major upgrades of the femtoslicing facility at BESSY II (Khan et al. , 2006) are reviewed, giving a tutorial on how elliptical-polarized ultrashort soft X-ray pulses from electron storage rings are generated at high repetition rates. Employing a 6 kHz femtosecond-laser system consisting of two amplifiers that are seeded by one Ti:Sa oscillator, the total average flux of photons of 100 fs duration (FWHM) has been increased by a factor of 120 to up to 10 6  photons s −1 (0.1% bandwidth) −1 on the sample in the range from 250 to 1400 eV. Thanks to a new beamline design, a factor of 20 enhanced flux and improvements of the stability together with the top-up mode of the accelerator have been achieved. The previously unavoidable problem of increased picosecond-background at higher repetition rates, caused by `halo' photons, has also been solved by hopping between different `camshaft' bunches in a dedicated fill pattern (`3+1 camshaft fill') of the storage ring. In addition to an increased X-ray performance at variable (linear and elliptical) polarization, the sample excitation in pump–probe experiments has been considerably extended using an optical parametric amplifier that supports the range from the near-UV to the far-IR regime. Dedicated endstations covering ultrafast magnetism experiments based on time-resolved X-ray circular dichroism have been either upgraded or, in the case of time-resolved resonant soft X-ray diffraction and reflection, newly constructed and adapted to femtoslicing requirements. Experiments at low temperatures down to 6 K and magnetic fields up to 0.5 T are supported. The FemtoSpeX facility is now operated as a 24 h user facility enabling a new class of experiments in ultrafast magnetism and in the field of transient phenomena and phase transitions in solids.
    Type of Medium: Online Resource
    ISSN: 1600-5775
    URL: Article
    DOI: 10.1107/S1600577514012247
    Language: Unknown
    Publisher: International Union of Crystallography (IUCr)
    Publication Date: 2014
    detail.hit.zdb_id: 2021413-3
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  • 10
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    Influence of Systemic Therapy on the Expression and Activity of Selected STAT Proteins in Prostate Cancer Tissue
    MDPI AG ; 2022
    In:  Life Vol. 12, No. 2 ( 2022-02-06), p. 240-
    Details
    In: Life, MDPI AG, Vol. 12, No. 2 ( 2022-02-06), p. 240-
    Abstract: Signal Transducer and Activator of Transcription (STAT) proteins have been identified as drivers of prostate cancer (PCa) progression and development of aggressive castration-resistant phenotypes. In particular, STAT3, 5, and 6 have been linked to resistance to androgen receptor inhibition and metastasis in in vitro and in vivo models. This descriptive study aimed to validate these preclinical data in tissue obtained from patients with PCa before and while under androgen-deprivation therapy. Therefore, STAT3, 5, and 6 expressions and activity were assessed by immunohistochemistry. The data revealed that STAT3 and 5 changed in PCa. However, there was no relationship between expression and survival. Moreover, due to the heterogeneous nature of PCa, the preclinical results could not be transferred congruently to the patient’s material. A pilot study with a longitudinal patient cohort could also show this heterogeneous influence of systemic therapy on STAT3, 5, and 6 expressions and activity. Even if the main mechanisms were validated, these data demonstrate the urge for better patient-near preclinical models. Therefore, these data reflect the need for investigations of STAT proteins in a longitudinal patient cohort to identify factors responsible for the diverse influence of system therapy on STAT expression.
    Type of Medium: Online Resource
    ISSN: 2075-1729
    URL: Article
    DOI: 10.3390/life12020240
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662250-6
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