Robust Unsupervised Learning via L-statistic Minimization.

Designing learning algorithms that are resistant to perturbations of the underlying data distribution is a problem of wide practical and theoretical importance. We present a general approach to this problem focusing on unsupervised learning. The key assumption is that the perturbing distribution is characterized by larger losses relative to a given class of admissible models. This is exploited by a general descent algorithm which minimizes an L - statistic criterion over the model class, weighting small losses more. Our analysis characterizes the robustness of the method in terms of bounds on the reconstruction error relative to the underlying unperturbed distribution. As a byproduct, we prove uniform convergence bounds with respect to the proposed criterion for several popular models in unsupervised learning, a result which may be of independent interest. Numerical experiments with \textsc{kmeans} clustering and principal subspace analysis demonstrate the effectiveness of our approach

Sex differences in wild-type transthyretin amyloidosis: An analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

INTRODUCTION: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is a progressive disease resulting from the accumulation of wild-type transthyretin (TTR) amyloid fibrils, and is diagnosed primarily in males. This analysis examined sex differences in patients with ATTRwt amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS). METHODS: THAOS is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of TTR mutations. THAOS data were analyzed to identify potential differences in demographic and clinical characteristics between males and females with ATTRwt amyloidosis (data cutoff: August 1, 2021). RESULTS: Of 1386 patients with ATTRwt amyloidosis, 84 (6%) were female and 1302 (94%) were male. Females had a higher median age at enrollment (80 vs. 78 years; p = 0.002) and symptom onset (75 vs. 73 years; p = 0.045) than males. Mean left ventricular (LV) ejection fraction was higher (53% vs. 48%; p = 0.001) and mean LV diastolic diameter lower (42 vs. 46 mm; p \u3c 0.001) in females versus males, but sex was not identified as a predictor of LV mean wall thickness adjusted for height (beta coefficient - 0.22; p = 0.460) or a predominantly cardiac phenotype (odds ratio 1.60; p = 0.191). Modified polyneuropathy disability scores differed between groups (p \u3c 0.001), with a larger proportion of scores ≥ IIIa among females (23% vs. 7%). CONCLUSIONS: Females with ATTRwt amyloidosis in THAOS tended to present at a later age and showed signs of less severe cardiac impairment and more severe walking impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745

Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis

Background: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis. Methods: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18. Results: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p < 0.001) and/or mometasone (p < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle (p < 0.001). Conclusion: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis

Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility

Background Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential. Methods In vitro assays were used to investigate heather’s anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition. Results Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage. Conclusions Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe

Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS):14-year update

Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). Results This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation. Conclusions This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease. ClinicalTrials.gov Identifier: NCT00628745.http://deepblue.lib.umich.edu/bitstream/2027.42/173793/1/13023_2022_Article_2359.pd

Yes, we also can! O desenvolvimento de iniciativas de consumo colaborativo no Brasil

The advances and dissemination of information and communication technologies enable the creation of new forms of sharing and the rise of platforms for collective practices which contribute for the development of new ways of consuming, such as the collaborative consumption. This form of consumption refers to the practice of sharing, commercial loans, rents and exchanges that take place mainly in the cyberspace. The practices involved in these systems are still recent in Brazil. Thus, this paper aims to understand the perception of users and organizations regarding the systems of collaborative consumption in the Brazilian context. To accomplish this, a qualitative research with an exploratory character was carried out through semi-structured interviews with managers and users of different systems of collaborative consumption. The results revealed that, even though the collaborative consumption is still in its beginning in Brazil, there is a positive scenario for the development of collective practices in this country. Besides that, many interesting results regarding risks, obstacles, benefits and the ways that trust could be generated within these systems were also identified. Thus, new opportunities are open for the collaborative consumption in the Brazilian context.Keywords: collaborative consumption, virtual platforms, Brazilian context.O avanço e disseminação das tecnologias de informação e comunicação proporcionam o surgimento de novas formas de compartilhamento e a ascensão de plataformas de práticas coletivas que contribuem para o desenvolvimento de novas formas de consumo, como o consumo colaborativo. Este tipo de consumo descreve a prática de partilha, empréstimos comerciais, aluguel e trocas realizados, principalmente, no ciberespaço. As práticas que envolvem estes sistemas ainda são recentes no Brasil. Neste sentido, este artigo tem o objetivo de compreender a percepção de usuários e organizações acerca dos sistemas de consumo colaborativo no contexto brasileiro. Para tanto, foi realizada uma pesquisa qualitativa, de caráter exploratório, por meio de entrevistas semiestruturadas com gestores de organizações e usuários de distintos sistemas de consumo colaborativo. Os resultados sugerem que, apesar de o consumo colaborativo estar em processo inicial no contexto brasileiro, existe um cenário positivo para o desenvolvimento das práticas coletivas no país. Além disso, foram encontrados resultados interessantes no que tange aos riscos, obstáculos e benefícios, bem como às formas como a confiança pode ser gerada nestes sistemas. Assim, novas oportunidades abrem-se ao consumo colaborativo no contexto brasileiro.Palavras-chave: consumo colaborativo, plataformas virtuais, contexto brasileiro

Yes, we also can! O desenvolvimento de iniciativas de consumo colaborativo no Brasil

The advances and dissemination of information and communication technologies enable the creation of new forms of sharing and the rise of platforms for collective practices which contribute for the development of new ways of consuming, such as the collaborative consumption. This form of consumption refers to the practice of sharing, commercial loans, rents and exchanges that take place mainly in the cyberspace. The practices involved in these systems are still recent in Brazil. Thus, this paper aims to understand the perception of users and organizations regarding the systems of collaborative consumption in the Brazilian context. To accomplish this, a qualitative research with an exploratory character was carried out through semi-structured interviews with managers and users of different systems of collaborative consumption. The results revealed that, even though the collaborative consumption is still in its beginning in Brazil, there is a positive scenario for the development of collective practices in this country. Besides that, many interesting results regarding risks, obstacles, benefits and the ways that trust could be generated within these systems were also identified. Thus, new opportunities are open for the collaborative consumption in the Brazilian context.Keywords: collaborative consumption, virtual platforms, Brazilian context.O avanço e disseminação das tecnologias de informação e comunicação proporcionam o surgimento de novas formas de compartilhamento e a ascensão de plataformas de práticas coletivas que contribuem para o desenvolvimento de novas formas de consumo, como o consumo colaborativo. Este tipo de consumo descreve a prática de partilha, empréstimos comerciais, aluguel e trocas realizados, principalmente, no ciberespaço. As práticas que envolvem estes sistemas ainda são recentes no Brasil. Neste sentido, este artigo tem o objetivo de compreender a percepção de usuários e organizações acerca dos sistemas de consumo colaborativo no contexto brasileiro. Para tanto, foi realizada uma pesquisa qualitativa, de caráter exploratório, por meio de entrevistas semiestruturadas com gestores de organizações e usuários de distintos sistemas de consumo colaborativo. Os resultados sugerem que, apesar de o consumo colaborativo estar em processo inicial no contexto brasileiro, existe um cenário positivo para o desenvolvimento das práticas coletivas no país. Além disso, foram encontrados resultados interessantes no que tange aos riscos, obstáculos e benefícios, bem como às formas como a confiança pode ser gerada nestes sistemas. Assim, novas oportunidades abrem-se ao consumo colaborativo no contexto brasileiro.Palavras-chave: consumo colaborativo, plataformas virtuais, contexto brasileiro

Diagnostic and Prognostic Implications of FGFR3(high)/Ki67(high) Papillary Bladder Cancers

Prognostic/therapeutic stratification of papillary urothelial cancers is solely based upon histology, despite activated FGFR3-signaling was found to be associated with low grade tumors and favorable outcome. However, there are FGFR3-overexpressing tumors showing high proliferation-a paradox of coexisting favorable and adverse features. Therefore, our study aimed to decipher the relevance of FGFR3-overexpression/proliferation for histopathological grading and risk stratification. N = 142 (n = 82 pTa, n = 42 pT1, n = 18 pT2-4) morphologically G1-G3 tumors were analyzed for immunohistochemical expression of FGFR3 and Ki67. Mutation analysis of FGFR3 and TP53 and FISH for FGFR3 amplification and rearrangement was performed. SPSS 23.0 was used for statistical analysis. Overall FGFR3(high)/Ki67(high) status (n = 58) resulted in a reduced Delta mean progression-free survival (PFS) (p < 0.01) of 63.92 months, and shorter progression-free survival (p < 0.01;mean PFS: 55.89 months) in pTa tumors (n = 50). FGFR3(mut)/TP53(mut) double mutations led to a reduced Delta mean PFS (p < 0.01) of 80.30 months in all tumors, and FGFR3(mut)/TP53(mut) pTa tumors presented a dramatically reduced PFS (p < 0.001;mean PFS: 5.00 months). Our results identified FGFR3(high)/Ki67(high) papillary pTa tumors as a subgroup with poor prognosis and encourage histological grading as high grade tumors. Tumor grading should possibly be augmented by immunohistochemical stainings and suitable clinical surveillance by endoscopy should be performed