A three-feature prediction model for metastasis-free survival after surgery of localized clear cell renal cell carcinoma

After surgery of localized renal cell carcinoma, over 20% of the patients will develop distant metastases. Our aim was to develop an easy-to-use prognostic model for predicting metastasis-free survival after radical or partial nephrectomy of localized clear cell RCC. Model training was performed on 196 patients. Right-censored metastasis-free survival was analysed using LASSO-regularized Cox regression, which identified three key prediction features. The model was validated in an external cohort of 714 patients. 55 (28%) and 134 (19%) patients developed distant metastases during the median postoperative follow-up of 6.3 years (interquartile range 3.4-8.6) and 5.4 years (4.0-7.6) in the training and validation cohort, respectively. Patients were stratified into clinically meaningful risk categories using only three features: tumor size, tumor grade and microvascular invasion, and a representative nomogram and a visual prediction surface were constructed using these features in Cox proportional hazards model. Concordance indices in the training and validation cohorts were 0.755 +/- 0.029 and 0.836 +/- 0.015 for our novel model, which were comparable to the C-indices of the original Leibovich prediction model (0.734 +/- 0.035 and 0.848 +/- 0.017, respectively). Thus, the presented model retains high accuracy while requiring only three features that are routinely collected and widely available.Peer reviewe

Limits on Enhanced Radio Wave Scattering by Supernova Remnants

We report multifrequency observations with the NRAO Very Long Baseline Array (VLBA) of the compact radio sources J0128+6306 and J0547+2721, which are viewed through the supernova remnants G127.1+0.5 and S147, respectively. Observations were made at frequencies of 1.427, 1.667, 2.271, and 4.987 GHz. The lines of sight to these sources pass through the shock wave and upstream and downstream turbulent layers of their respective supernova remnants, and thus might detect cosmic-ray generated turbulence produced during the Fermi acceleration process. For both sources, we detect interstellar scattering, characterized by a component of the angular size which scales as the square of the observing wavelength. The magnitude of the scattering is characterized by an effective scattering angular size theta_S0 at a frequency of 1 GHz of 13.2 +/- 2.6 milliarcseconds (mas) for J0128+6306 and 6.7 +/- 2.2 mas for J0547+2721. These angular sizes are consistent with the ``incidental'' scattering for any line of sight out of the galaxy at similar galactic latitudes and longitudes. There is therefore no evidence for enhanced turbulence at these supernova remnants. We establish upper limits to the supernova remnant-associated scattering measures of 8.1-14.8 m^-20/3-pc for J0128+6306 and 3.0 m^-20/3-pc for J0547+2721.Comment: To be published in ApJ, 25 pages, 4 figures, 2 table

A three-feature prediction model for metastasis-free survival after surgery of localized clear cell renal cell carcinoma

After surgery of localized renal cell carcinoma, over 20% of the patients will develop distant metastases. Our aim was to develop an easy-to-use prognostic model for predicting metastasis-free survival after radical or partial nephrectomy of localized clear cell RCC. Model training was performed on 196 patients. Right-censored metastasis-free survival was analysed using LASSO-regularized Cox regression, which identified three key prediction features. The model was validated in an external cohort of 714 patients. 55 (28%) and 134 (19%) patients developed distant metastases during the median postoperative follow-up of 6.3 years (interquartile range 3.4-8.6) and 5.4 years (4.0-7.6) in the training and validation cohort, respectively. Patients were stratified into clinically meaningful risk categories using only three features: tumor size, tumor grade and microvascular invasion, and a representative nomogram and a visual prediction surface were constructed using these features in Cox proportional hazards model. Concordance indices in the training and validation cohorts were 0.755 +/- 0.029 and 0.836 +/- 0.015 for our novel model, which were comparable to the C-indices of the original Leibovich prediction model (0.734 +/- 0.035 and 0.848 +/- 0.017, respectively). Thus, the presented model retains high accuracy while requiring only three features that are routinely collected and widely available

Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries\u27 societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household\u27s food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p \u3c 0.001) and increased in the Gulf Cooperation Council countries including Bahrain (p = 0.003), Egypt (p \u3c 0.001) and United Arab Emirates (p = 0.013). A decline in the household\u27s dietary diversity was observed in Australia (p \u3c 0.001), in South Africa including Uganda (p \u3c 0.001), in Europe including Belgium (p \u3c 0.001), Denmark (p = 0.002), Finland (p \u3c 0.001) and Netherland (p = 0.027) and in South America including Ecuador (p \u3c 0.001), Brazil (p \u3c 0.001), Mexico (p \u3c 0.0001) and Peru (p \u3c 0.001). Middle and older ages [OR = 1.2; 95 % CI = [1.125–1.426] [OR = 2.5; 95 % CI = [1.951–3.064], being a woman [OR = 1.2; 95 % CI = [1.117–1.367], having a high education (p \u3c 0.001), and showing amelioration in food-related behaviors [OR = 1.4; 95 % CI = [1.292–1.709] were all linked to having a higher dietary diversity. Conclusion: The minor to moderate changes in food consumption patterns observed across the 38 countries within relatively short time frames could become lasting, leading to a significant and prolonged reduction in dietary diversity, as demonstrated by our findings

Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries' societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household's food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p < 0.001) and increased in the Gulf Cooperation Council countries including Bahrain (p = 0.003), Egypt (p < 0.001) and United Arab Emirates (p = 0.013). A decline in the household's dietary diversity was observed in Australia (p < 0.001), in South Africa including Uganda (p < 0.001), in Europe including Belgium (p < 0.001), Denmark (p = 0.002), Finland (p < 0.001) and Netherland (p = 0.027) and in South America including Ecuador (p < 0.001), Brazil (p < 0.001), Mexico (p < 0.0001) and Peru (p < 0.001). Middle and older ages [OR = 1.2; 95 % CI = [1.125–1.426] [OR = 2.5; 95 % CI = [1.951–3.064], being a woman [OR = 1.2; 95 % CI = [1.117–1.367], having a high education (p < 0.001), and showing amelioration in food-related behaviors [OR = 1.4; 95 % CI = [1.292–1.709] were all linked to having a higher dietary diversity. Conclusion: The minor to moderate changes in food consumption patterns observed across the 38 countries within relatively short time frames could become lasting, leading to a significant and prolonged reduction in dietary diversity, as demonstrated by our findings.Revisión por pare

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

Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 – 2018

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species

Neuronostatin, connective tissue growth factor and glycogen synthase kinase 3β in cardiac physiology and disease

Abstract Cardiovascular diseases are the leading cause of death in Western countries. The aim of my thesis was to increase understanding of the signaling pathways regulating progression of cardiac remodeling from myocardial infarction injury and cardiac hypertrophy to heart failure. In these preclinical studies, I focused on the factors regulating cardiomyocyte survival, hypertrophy and extracellular matrix modulation. There were three different factors in my studies; neuronostatin (NST), connective tissue growth factor (CTGF) and glycogen synthase kinase 3β (GSK3β). NST is a peptide found in various organs, including heart. I found that NST has an attenuating effect on endothelin-1 -induced left ventricular (LV) contractility in isolated perfused rat heart which is also followed by increased phosphorylation of p38 mitogen activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). NST also reduced survival of the cultured cardiomyocytes, which was further compromised by JNK inhibition. CTGF has a physiological role in tissue repair and it is overexpressed in almost all fibrotic diseases as well as in cardiac fibrosis and atherosclerosis. In my studies therapy with a CTGF monoclonal antibody (mAb) improved survival, attenuated infarct expansion and preserved LV systolic function during cardiac repair after myocardial infarction (MI) in mice. LV fibrosis, MI-induced cardiomyocyte hypertrophy and increase in LV mass were all attenuated with CTGF mAb treatment during post-MI LV remodeling. These changes were associated with reduced inflammatory and pro-fibrotic gene activation and enhanced expression of genes related to cardiac development and/or repair. In vitro -studies with human fibroblasts showed a role for JNK in reducing collagen production by the CTGF mAb. GSK3β is a serine/threonine kinase first identified as a negative regulator of glycogen synthase. It also has an important role in cardiac hypertrophy and cell death. My key finding was that phosphorylation of the GSK3β S389 site is cardioprotective and antihypertrophic in cultured cardiomyocytes. In conclusion, these three factors, NST, CTGF, and GSK3β, contribute to cardiomyocyte survival, hypertrophic response and fibrotic response of cardiac remodeling. This knowledge may eventually lead to development of targeted therapies to decrease and prevent cardiac injury.Tiivistelmä Sydän- ja verisuonitaudit ovat yleisin kuolinsyy länsimaissa. Väitöskirjani tarkoitus on lisätä ymmärrystä sydämen solujen signaalireiteistä, jotka säätelevät sydäninfarktista ja sydämen vasemman kammion liikakasvusta seuraavaa vasemman kammion haitallista uudelleen muovautumista ja johtavat sydämen vajaatoimintaan. Prekliinisessä tutkimuksessani keskityin tekijöihin, jotka säätelevät sydänlihassolun selviytymistä, liikakasvua ja soluväliaineen muokkausta. Tutkin kolmea eri tekijää: neuronostatiinia (NST), sidekudoksen kasvutekijää (CTGF) ja glykogeenisyntaasikinaasi 3β:tä (GSK3β). NST on peptidi, jota on löydetty useista elimistä, myös sydämestä. Tutkimuksissani NST heikensi endoteliini-1:n indusoimaa sydämen supistuvuutta rotan eristetyssä perfusoidussa sydämessä lisäten myös p38 mitogeeniaktivoituvan proteiinikinaasin (p38 MAPK) ja JNK:n (engl. c-Jun N-terminal kinase) fosforylaatiota. NST lisäsi myös viljeltyjen sydänlihassolujen kuolleisuutta, jota JNK:n estäminen vielä lisäsi. CTGF:lla on fysiologinen rooli kudosten korjautumisessa, ja sen määrä on lisääntynyt lähes kaikissa sidekudosta lisäävissä sairauksissa, myös sidekudostuvassa sydämessä ja valtimokovettumataudissa. Hiiren kokeellisen sydäninfarktin hoito CTGF:n monoklonaalisella vasta-aineella infarktin korjaantumisvaiheessa paransi eloonjäämistä, vähensi infarktin laajenemista ja hidasti sydämen toiminnan heikkenemistä. Vasemman kammion uudelleen muovautumisen vaiheessa hoito vähensi sydämen sidekudostumista ja liikakasvua. Taustalla nähtiin vähäisempi nousu tulehduksellisissa ja sidekudosta lisäävissä geeneissä ja lisääntynyt nousu sydämen kehitykseen ja korjautumiseen liittyvissä geeneissä. Vasta-aineella hoidetuissa viljellyissä ihmisen fibroblastisoluissa JNK näytti välittävän vähentynyttä kollageenin eritystä. GSK3β on seriini-treoniini -kinaasi, jonka ensin havaittiin säätelevän negatiivisesti glykogeenisyntaasia. Sillä on myös merkittävä rooli sydämen vasemman kammion liikakasvussa ja solukuolemassa. Tärkein löydökseni on, että eristetyissä sydänlihassoluissa GSK3β S389 -kohdan fosforylaatio suojaa soluja solukuolemalta ja liikakasvulta. Johtopäätöksenä voin todeta näiden kolmen tutkimani tekijän, NST:n, CTGF:n ja GSK3β:n, olevan osallisina sydämen vasemman kammion uudelleen muovautumisessa; solukuolemassa, liikakasvussa ja sidekudosvasteessa. Tämän väitöskirjan tuoma lisätieto voi johtaa paremmin kohdennettuihin sydänvaurioiden hoitoihin