Presentation and medical management of peripheral arterial disease in general practice: rationale, aims, design and baseline results of the PACE-PAD Study

Background: Peripheral arterial disease (PAD) is highly prevalent among individuals of higher age or those with one or more cardiovascular risk factors. Screening for PAD is recommended, since it is often linked to atherothrombotic manifestations in the coronary or carotid circulation and associated with a substantial increase in all-cause and cardiovascular mortality. We aimed to assess patients with newly diagnosed, suspected and confirmed PAD in the primary care setting with regards to clinical characteristics, diagnostic and therapeutic management (including referral to specialists), and medium-term outcomes. Methods: This was a multicentre, prospective, observational cohort study with a cross-sectional and a longitudinal part. A total of 2,781 general practitioners across Germany were cluster randomised to document five consecutive patients each in one of the strata: (1) patients with intermittent claudication (IC) or other typical PAD-related complaints (group A) or (2) patients >55 years of age with one or more risk factors (group B) for PAD (current smoking, diabetes, previous myocardial infection and/or previous stroke). Patients with confirmed PAD will be followed up for diagnostic procedures, therapy and vascular events over 18 months. Results: In group A, a total of 2,131 patients with suspected PAD (80.1% confirmed, 75.9% with referral to specialists) and in group B 9,921 patients were included (44.6% confirmed, 54.6% referral). The ankle-brachial index was calculated in 41.3% and 33.5% only. Mean age was 66.6 years (group A) and 68.4 years (group B), respectively. Vascular risk factors were prevalent in both groups, in particular smoking (group A 44.6%, group B 44.4%), hypertension (73.2 and 78.1%), hypercholesterolaemia (64.6 and 70.6%) and diabetes mellitus (41.7 and 60.6%). Concomitant atherothrombotic morbidities were frequent in both groups. In patients with the respective diseases, antihypertensive, antidiabetic, lipid-lowering and antithrombotic therapies were prescribed in group A in 96.6, 96.0, 91.1 and 89.7% and in group B in 98.3, 97.4, 94.1 and 91.2%. Conclusion: The cross-sectional part of the study indicates a substantial burden of disease in PAD patients in primary care. Treatment rates appear to have improved compared to earlier surveys. In the follow-up period, outcomes of these patients and their association with disease stages, guideline-oriented treatment or patient compliance and disease-coping strategies, among other factors, will be determined

Presenilin-Dependent Receptor Processing Is Required for Axon Guidance

SummaryThe Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-β precursor protein, contributing to the pathogenesis of neurodegeneration that is characterized by loss of neuronal connections, but the role of Presenilin in establishing neuronal connections is less clear. Through a forward genetic screen in mice for recessive genes affecting motor neurons, we identified the Columbus allele, which disrupts motor axon projections from the spinal cord. We mapped this mutation to the Presenilin-1 gene. Motor neurons and commissural interneurons in Columbus mutants lacking Presenilin-1 acquire an inappropriate attraction to Netrin produced by the floor plate because of an accumulation of DCC receptor fragments within the membrane that are insensitive to Slit/Robo silencing. Our findings reveal that Presenilin-dependent DCC receptor processing coordinates the interplay between Netrin/DCC and Slit/Robo signaling. Thus, Presenilin is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity

Outcomes of medical management of peripheral arterial disease in general practice: follow-up results of the PACE-PAD Study

Aim: Peripheral arterial disease (PAD), a marker of elevated vascular risk, is highly prevalent in general practice. We aimed to investigate patient characteristics and outcomes of PAD patients treated according to the guidelines versus those who were not. Methods: The Patient Care Evaluation-Peripheral Arterial Disease Study (PACE-PAD) was a multicenter, cluster randomized, prospective, longitudinal cohort study of patients with PAD in primary care, who were followed up for death or vascular events over 18 months. Guideline orientation was assumed if patients received anticoagulant/antiplatelet therapy, exercise training, and (if applicable) advice for smoking cessation and therapy of diabetes mellitus, hypertension, or hypercholesterolemia, respectively. Results: Of the 5,099 PAD patients (mean age 68.0 ± 9.0 years, 68.5% male subjects) who were followed up, 22.5, 34.6, 30.1, 7.8, and 3.5% (1.5% not specified) were in Fontaine stages I, IIa, IIb, III, and IV. Comprehensive guideline orientation was reported in 28.4% only; however, patients in lower Fontaine stages received guideline-oriented therapy more often (I: 30.3%, IIa: 31.6%, IIb: 29.1%, III: 9.8%, IV: 18.0%). During 18 months, 457 patients died (224 due to cerebrovascular or coronary deaths), 319 had unstable angina pectoris, 116 myocardial infarction, and 140 an ischemic stroke event. In total, 24% of patients had experienced any vascular event (19.1% a first event). Event rates did not differ between patients treated according to guidelines and those who were not. Conclusion: The present PAD cohort was a high-risk sample with an unexpectedly high rate of deaths and vascular events. While physicians appear to focus on the treatment of individual risk factors, rates of comprehensive PAD management in line with guideline recommendations are still suboptimal. Factors contributing to the lacking difference between outcomes in the guideline-oriented and non-guideline-oriented groups may comprise low treatment intensity or other reasons for unsatisfactory effect of treatment, misclassification of events, and patient’s noncompliance with therapy

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

The association between active participation in a sports club, physical activity and social network on the development of lung cancer in smokers: a case-control study

<p>Abstract</p> <p>Background</p> <p>This study analyses the effect of active participation in a sports club, physical activity and social networks on the development of lung cancer in patients who smoke. Our hypothesis is that study participants who lack social networks and do not actively participate in a sports club are at a greater risk for lung cancer than those who do.</p> <p>Methods</p> <p>Data for the study were taken from the <b>Co</b>logne <b>Smo</b>king <b>S</b>tudy (<b>CoSmoS</b>), a retrospective case-control study examining potential psychosocial risk factors for the development of lung cancer. Our sample consisted of n = 158 participants who had suffered lung cancer (diagnosis in the patient document) and n = 144 control group participants. Both groups had a history of smoking.</p> <p>Data on social networks were collected by asking participants whether they participated in a sports club and about the number of friends and relatives in their social environment. In addition, sociodemographic data (gender, age, education, marital status, residence and religion), physical activity and data on pack years (the cumulative number of cigarettes smoked by an individual, calculated by multiplying the number of cigarettes smoked per day by the number of years the person has smoked divided by 20) were collected to control for potential confounders. Logistic regression was used for the statistical analysis.</p> <p>Results</p> <p>The results reveal that participants who are physically active are at a lower risk of lung cancer than those who are not (adjusted OR = 0.53*; CI = 0.29-0.97). Older age and lower education seem also to be risk factors for the development of lung cancer. The extent of smoking, furthermore, measured by pack years is statistically significant. Active participation in a sports club, number of friends and relatives had no statistically significant influence on the development of the cancer.</p> <p>Conclusions</p> <p>The results of the study suggest that there is a lower risk for physically active participants to develop lung cancer. In the study sample, physical activity seemed to have a greater protective effect than participation in a sports club or social network of friends and relatives. Further studies have to investigate in more detail physical activity and other club participations.</p

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota)

55 Pág.In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.This work was supported in part through the Laulima Government Solutions, LLC, prime contract with the U.S. National Institute of Allergy and Infec tious Diseases (NIAID) under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC, under Contract No. HHSN272201800013C. U.J.B. was supported by the Division of Intramural Resarch, NIAID. This work was also funded in part by Contract No. HSHQDC15-C-00064 awarded by DHS S and T for the management and operation of The National Biodefense Analysis and Countermeasures Centre, a federally funded research and development centre operated by the Battelle National Biodefense Institute (V.W.); and NIH contract HHSN272201000040I/HHSN27200004/D04 and grant R24AI120942 (N.V., R.B.T.). S.S. acknowl edges support from the Mississippi Agricultural and Forestry Experiment Station (MAFES), USDA-ARS project 58-6066-9-033 and the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch Project, under Accession Number 1021494. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of the Army, the U.S. Department of Defence, the U.S. Department of Health and Human Services, including the Centres for Disease Control and Prevention, the U.S. Department of Homeland Security (DHS) Science and Technology Directorate (S and T), or of the institutions and companies affiliated with the authors. In no event shall any of these entities have any responsibility or liability for any use, misuse, inability to use, or reliance upon the information contained herein. The U.S. departments do not endorse any products or commercial services mentioned in this publication. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S.Government retains a non-exclusive, paid up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. Government purposes.Peer reviewe