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Extensive research efforts are being carried out to evaluate and improve the reliability of computing devices, either through beam experiments or simulation-based fault injection. Unfortunately, it is still largely unclear to which extend fault injection can provide an accurate error rate estimation at early stages and if beam experiments can be used to identify the weakest resources in a device. The challenges associated with reliability evaluation grow with the increase of complexity of the hardware and the software. In this paper, we combine and analyze data gathered with extensive beam experiments (on the final physical CPU hardware) and microarchitectural fault injections (on early microarchitectural CPU models). We target a standalone Arm Cortex-A5 and an Arm Cortex-A9 integrated in an SoC and evaluate their reliability in bare-metal and Linux-based configurations. We find that both the SoC integration and the OS presence increase the system DUEs (Detected Unrecoverable Errors) rate (for different reasons) but do not significantly impact the SDCs (Silent Data Corruptions) rate which is solely attributed to the CPU core. Our reliability analysis demonstrates that, even considering SoC integration and OS inclusion, early, pre-silicon microarchitecture-level fault injection delivers accurate SDC rates estimations and lower bounds for the DUE rates.

BackgroundO’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

The objective of this study was to quantify intraoperative bleeding in patients with cirrhosis and correlate it with clinical characteristics and laboratory coagulation tests.A case-control study was carried out with 74 patients with cirrhosis who were submitted to preoperative coagulation tests (complete blood count, platelet count, prothrombin time/international normalized ratio, thrombin time, activated partial thrombin time, platelet aggregation, fibrinogen, protein C, protein S, antithrombin, and von Willebrand factor level and activity). The levels of nitrogen compounds that can affect the platelet function were determined in saliva and blood by using automated enzymatic-colorimetric assays.Patients with cirrhosis had changes in almost all coagulation tests. The average volumes of intraoperative bleeding and blood lost per minute in the study group (5.36 mL/min and 0.19 mL/min, respectively) were greater than those in the control group (3.05 mL/min and 0.11 mL/min, respectively; P.05). In the control group, ascites (P = .012) and presence of periapical lesion (0.034) were positively correlated with bleeding (mL/min). With regard to coagulation tests and nitrogen compounds, only a positively moderate correlation with the platelet aggregation test was observed.No patients had hemorrhagic events and it was not possible to correlate a greater amount of bleeding with coagulation tests or nitrogen compounds in the study group.

Introduction Cigarettes are the main cause of preventable death in the world, and primary health care services can contribute to the management of this habit. Objective To describe and analyze the factors associated with tobacco cessation in groups of smokers in primary health care. Methods The present is a cross-sectional study conducted in 12 primary health care units from July 2016 to May 2017. We investigated sociodemographic and health variables, as well as smoking characteristics and different interventions for tobacco cessation, with the outcome being studied and analyzed after the fourth group care session. Results We evaluated 329 smokers, of which 182 quit smoking after the fourth interview. Most of the individuals who quit smoking were women (n = 121, 66.5%), with a monthly income of 2 to 5 minimum wages (n = 88, 77.9%). After the multivariable analysis, we observed that tobacco cessation was significantly associated with depression (prevalence ratio [PR] = 1.11; 95% confidence interval [95%CI] = 1.02 to 1.22), as well as with belonging to the groups which used as approaches motivational interviewing (PR = 1.21; 95%CI = 1.13 to 2.01), patches (PR = 1.36; 95%CI = 1.24 to 1.48), and bupropion (PR = 1.16; 95%CI = 1.03 to 1.31). Conclusion Primary health care is the ideal site for the reduction of smoking rates, given that different technologies may be applicable and useful for tobacco cessation. The comprehensiveness and longitudinal care offered in primary care may provide opportunities for health professionals to understand which is the best technology for each health system user, thus contributing to personalized care.

To assess if microstructural bone lesions in individuals at risk of developing rheumatoid arthritis (RA) are related to the spectrum of anti-modified protein antibodies (AMPAs) and affect the risk of developing RA.Cortical microchannels as well as cortical and trabecular bone mineral density (BMD) volumes (expressed as mg hydroxyapatite/cmSubjects at risk of developing RA (n = 75) who had broad-spectrum AMPAs (6-8 reactivities) had significantly more severe microstructural changes, including a higher mean ± SD number of cortical microchannels per joint (95 ± 3) and lower total volumetric BMD (vBMD; 265 ± 45), trabecular vBMD (176 ± 42), and cortical vBMD (585 ± 138), than those with moderate AMPA reactivity (3-5 reactivities) (number of cortical microchannels, 79 ± 30; total vBMD, 293 ± 33; trabecular vBMD, 195 ± 32; and cortical vBMD, 627 ± 91) and those with narrow AMPA reactivity (1-2 reactivities) (number of cortical microchannels, 47 ± 20; total vBMD, 311 ± 34; trabecular vBMD, 211 ± 30; and cortical vBMD, 674 ± 56). Progressors to RA had significantly higher numbers of cortical microchannels (103 ± 30 versus 71 ± 35) and lower bone volume (258 ± 37 versus 295 ± 34) compared to nonprogressors. Furthermore, rate of progression to RA was high in subjects with broad AMPA reactivity (48%) versus those with medium AMPA reactivity (26%) or narrow AMPA reactivity (0%), as well as in those with a high number of cortical microchannels (44%) versus those with a low number of cortical microchannels (10%).Microstructural changes in individuals at risk of RA are associated with broad-spectrum autoimmunity and predict the onset of RA. These data support the concept of structural priming of joints by autoimmunity before the onset of the inflammatory phase of the disease.

Summary Background Patients with COVID-19 pneumonia can have increased inflammation and elevated cytokines, including interleukin (IL)-6, which might be deleterious. Thus, sarilumab, a high-affinity anti-IL-6 receptor antibody, might improve the outcome of patients with moderate-to-severe COVID-19 pneumonia. Methods We did a multicentric, open-label, Bayesian randomised, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance and a WHO Clinical Progression Scale [CPS] score of 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomisation list stratified on centre and with blocks randomly selected among 2 and 4, to receive usual care plus 400 mg of sarilumab intravenously on day 1 and on day 3 if clinically indicated (sarilumab group) or usual care alone (usual care group). Primary outcomes were the proportion of patients with WHO-CPS scores greater than 5 on the 10-point scale on day 4 and survival without invasive or non-invasive ventilation at day 14. This completed trial is closed to new participants and is registered with ClinicalTrials.gov , NCT04324073 . Findings 165 patients were recruited from March 27 to April 6, 2020, and 148 patients were randomised (68 patients to the sarilumab group and 80 to the usual care group) and followed up for 90 days. Median age was 61·7 years [IQR 53·0–71·1] in the sarilumab group and 62·8 years [56·0–71·7] in the usual care group. In the sarilumab group 49 (72%) of 68 were men and in the usual care group 59 (78%) of 76 were men. Four patients in the usual care group withdrew consent and were not analysed. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0·2%; 90% credible interval [CrI] −11·7 to 12·2), with a posterior probability of absolute risk difference greater than 0 of 48·9%. At day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died, (median posterior hazard ratio [HR] 1·10; 90% CrI 0·69–1·74) with a posterior probability HR greater than 1 of 37·4%. Serious adverse events occurred in 27 (40%) patients in the sarilumab group and 28 (37%) patients in the usual care group (p=0·73). Interpretation Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival. Funding Assistance publique—Hopitaux de Paris

Objective To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk for the progression to psoriatic arthritis (PsA). Methods Prospective cohort study on psoriasis patients without clinical evidence of musculoskeletal involvement receiving baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intra-articular sites by high-resolution peripheral quantitative computed tomography (HR-pQCT). Adjusted relative risks of developing PSA associated with baseline volumetric bone density and the presence of structural entheseal lesions were calculated using multivariable Cox regression models. Results The cohort included 114 psoriasis patients (M/F 72/42) with a mean (SD) follow-up duration of 28.2 (17.7) months, during which 24 patients developed PsA (9.7 /100 patient-years, 95%CI 6.2 to 14.5). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4/100 patient-years, 95%CI 12.5 to 34.3, HR 5.10, 95%CI 1.53 to 16.99, p=0.008). With respect to vBMD, a 1-standard deviation increase in entheseal, but not intra-articular vBMD was associated with an approximate 30% reduced risk to progress to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per SD, 95%CI 0.14 to 0.71), and remained robust after multiple imputation of missing data (HR 0.64, 95%CI 0.42 to 0.98). Conclusion Presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.

OBJECTIVE To analyze what are the methods for working length (WLD) determination taught for undergraduate students in Brazilian Dental Schools and the perception of professors about the use of electronic WL determination in the clinical practice. METHODOLOGY An online questionnaire with eighteen closed questions was sent to 209 Schools of Dentistry in Brazil using the Google Forms Platform. The questionnaire was structured to analyze the perception of professors in the department of​endodontics about the method of working length determination taught in undergraduate courses in Dentistry. The data collected in the questionnaires were transferred to an Excel® spreadsheet and analyzed using absolute and relative frequencies. The non-parametric Mann Whitney test was used to compare groups. RESULTS Of the 209 schools contacted, 41 (19.61%) returned answers to the questionnaire. According to professors, electronic working length (WL) determination had a shorter length of time to perform it (P

This paper aimed to identify farm business models in family and nonfamily succession focused on continuity. Three databases and 77 selected papers were collected for analysis. Family and nonfamily models characterized 13 possibilities for business continuity in farm succession. The findings showed that each case is unique, including business characteristics, the institutional environment, and its stakeholders. Having one or more family heir interested in taking over as a successor is related to the economic potential of the business and the family governance form to minimize intrafamily conflicts. Solutions can provide financial security and emotional stability to older farmers. Lack of information, poorly drafted contracts, or insecurity to organize a succession process within or outside the family members can lead farmers not to pass on his business to others when his capability is wearing out.

Treatment of acute ischemic stroke (AIS) with intravenous alteplase within 4.5 h of symptom onset is associated with neurologic improvement. High baseline blood pressure (BP) and BP variability during the first 24 h of AIS is associated with increased early adverse events and death. The purpose of this study is to characterize the incidence of poor neurologic outcome in patients treated with alteplase for AIS who received antihypertensive medications prior to and within the first 24 h following alteplase administration compared with patients who did not.This was a multicenter, retrospective cohort of patients18 years diagnosed with AIS from January 1, 2011 through December 31, 2015 who received one or more antihypertensive medication in the first 24 h of AIS in patients receiving alteplase compared to controls. The primary endpoint was poor neurologic outcome at 90 days, according to modified Rankin Scale ≥3. Univariate analysis was conducted using Chi-square, Fisher's exact test, or Mann-Whitney U test. Multivariable logistic regression was conducted to determine independent predictors of poor outcome.Of the 587 patients evaluated, 351 (59.7%) were included, of which 127 (36.2%) received antihypertensive(s). More patients in the antihypertensive treatment group had a history of hypertension (88.2% vs. 69.6%, p0.01), diabetes (37% vs. 25.5%, p = 0.03) and chronic kidney disease (19.7% vs. 8.5%, p0.01). Intravenous push labetalol was most commonly administered (81.2%), followed by nicardipine (44.1%), and hydralazine (22%). More patients in the antihypertensive treatment group experienced poor neurologic outcome at 90 days (53.5% vs. 38.8%, p0.01), however, this finding was not observed after multivariable logistic regression.Antihypertensive treatment in the first 24 h of AIS was associated with poor neurologic outcomes at 90 days. However, after controlling for other clinical factors in a multivariable logistic regression, this association was no longer observed.

Histiocytic neoplasms, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), present a diagnostic challenge due to nonspecific fibroinflammatory infiltrates and a diverse clinical presentation. The pathologist can play a key role in classification of these disorders through multidisciplinary collaboration and correlation of pathologic features with clinical and radiologic findings. The histopathologic differential diagnosis is broad, requiring knowledge of the possible diagnoses at each specific anatomic site, and a careful assessment to exclude other inflammatory and neoplastic disorders. An immunohistochemistry panel including CD163, CD1a, langerin, S100, Factor XIIIa, OCT2, and BRAF V600E can provide definitive diagnosis in LCH and RDD, whereas ECD requires classic clinical features as well as confirmation of an activating MAPK pathway mutation by genetic studies.

Objective This study evaluated the risk of the hereditary breast and ovarian cancer (HBOC) syndrome in patients with breast cancer by using the Family History Screening 7 (FHS-7) tool, a validated low-cost questionnaire with high sensitivity able to screen the HBOC risk in the population. Methods Women diagnosed with breast cancer (n=101) assisted by the Unified Health System at the 8th Regional Health Municipal Office of the state of Paraná answered the FHS-7, and the results were analyzed using IBM SPSS Statistics for Windows, Version 25.0. software (IBM Corp., Armonk, NY, USA). Results The risk of HBOC was 19.80% (n=20). Patients at risk exhibited aggressive tumor characteristics, such as high-grade tumors (30%), presence of angiolymphatic emboli (35%), and premenopausal at diagnosis (50%). Significant associations between the prevalence of high-grade tumors were observed inwomen younger than 50 years at diagnosis with HBOC (p=0.003). Conclusion Our findings suggest a possible family inheritance associated with worse clinical features in women with breast cancer in this population, indicating that HBOC investigation can be initially performed with low-cost instruments such as FHS-7. Resumo Objetivo Este estudo avaliou o risco da síndrome hereditária de câncer de mama e ovário (HBOC, na sigla em inglês) em pacientes com câncer de mama utilizando a ferramenta Familial History Screening 7 (FHS-7), um questionário validado de baixo custo e com alta sensibilidade capaz de rastrear o risco de HBOC na população. Métodos Mulheres diagnosticadas com câncer de mama (n=101) assistidas pelo Sistema Único de Saúde da 8ª Regional de Saúde do estado do Paraná responderam ao questionário FHS-7, e os resultados foram analisados pelo software IBM SPSS for Windows, Version 25.0. (IBM Corp., Armonk, NY, EUA). Resultados A ocorrência do risco de HBOC foi de 19,80% (n=20). Pacientes em risco exibiram características agressivas do tumor como tumores de alto grau (30%), presença de êmbolos angiolinfáticos (35%) e pré-menopausa ao diagnóstico (50%). Associações significantes foram observadas entre a prevalência de tumores de alto grau e diagnóstico abaixo de 50 anos no grupo HBOC (p=0.003). Conclusão Nossos achados sugerem uma possível herança familiar associada a piores características clínicas em mulheres com câncer de mama nessa população, indicando que a investigação de HBOC pode ser realizada, inicialmente, com instrumentos de baixo custo, como o FHS-7.

Summary Background Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. Methods RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score ClinicalTrials.gov ( NCT02779114 ). Findings Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3–90·0) in the continue group, 58·6% (49·2–70·0) in the taper group, and 43·3% (34·6–55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69–5·40; p=0.0003) for the taper group and 4·34 (2·48–7·60; p Interpretation Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. Funding None.

We report a case of diffuse melanosis secondary to metastatic malignant melanoma in a Nelore bull. Clinical signs included isolation from the herd, epistaxis, hyperthermia, pale ocular membranes, mucoid diarrhea and dark urine. Despite anti-inflammatory and antibiotic therapy, the bull died 45 days after the onset of the clinical signs. The most striking lesion was diffuse black discoloration to the visceral organs including liver, spleen, lungs, lymph nodes, and kidneys; all these affect organs were moderately enlarged”. The urine was black. Histologically, 50-80% of the parenchyma of the liver, spleen and lymph nodes was obliterated by aggregates of melanin-loaded neoplastic melanocytes. Those neoplastic cells also occurred within capillaries of the liver, spleen, lymph nodes, urinary bladder, lungs and kidneys. Immunohistochemistry of neoplastic melanocytes was positive for Melan A and PNL2 markers. Abundant brown to black pigment was found in melanophages in the lungs, confirmed by IBA1 immunohistochemistry.