In current guidelines, thiopurines are still recommended as first-line maintenance therapy for patients with Crohn’s disease (CD). Due to their lack of immunogenicity, oral administration route and low costs, thiopurines are an attractive first-line treatment option. However, in recent studies the position of thiopurine monotherapy in CD has been questioned as a result of relatively lower overall effectiveness rates compared to ulcerative colitis. Real-world long-term effectiveness data substantiating the use and position of thiopurines in CD management remain sparse. We assessed long-term effectiveness of thiopurine monotherapy in CD using the population-based IBD South-Limburg (IBDSL) cohort. All CD patients in the IBDSL cohort starting thiopurine monotherapy as first-line maintenance therapy between 1991–2014 were included. Thiopurine monotherapy was defined effective if either: (1) no escalation to biological treatment, (2) no course of corticosteroids, (3) no resective surgery or, (4) no hospitalization for active disease was required whilst on thiopurine treatment. Patients with early treatment discontinuation (i.e. <3 months) were identified, including reason of discontinuation. Long-term effectiveness was assessed adjusting for differences in follow-up between patients using Kaplan-Meier analysis. Potential risk factors for therapy failure were identified using Cox regression. In total, 643/1162 (55.3%) CD patients (median follow-up: 8.5 years IQR 5.0–13.2) received first-line thiopurine monotherapy after a median of 9.7 months (IQR 3.2–31.3) after diagnosis. Therapy was discontinued within three months in 164 patients (25.5%), mainly due to adverse events [Figure 1]. Thiopurine monotherapy was effective for the duration of treatment in 229/479 (35.6%) patients, corresponding to estimated effectiveness rates of 62.9%, 43.9% and 31.2% after 1, 5 and 10 years, respectively [Figure 1–2]. No significant difference in effectiveness was observed after stratifying for era of thiopurine initiation (pre-biological (1991–1998) vs. biological (>1999) era, p=0.84). Factors associated with thiopurine failure were stricturing disease (aHR 1.41, 95%CI 1.01–1.96) and upper GI involvement (aHR 1.52, 95%CI 1.02–2.28) at diagnosis. During follow-up, 40/229 patients with a durable response discontinued treatment due to quiescent disease. Of these, 35 patients (87.5%) remained without treatment 24 months after discontinuation. Real-world data from this population-based study demonstrate that thiopurine monotherapy remains an effective and durable first-line treatment option for CD, even in the biological era. These results should be considered in the ongoing discussion regarding the position of thiopurine therapy.

BACKGROUND falls and fall-related injuries are common in older adults, have negative effects both on quality of life and functional independence and are associated with increased morbidity, mortality and health care costs. Current clinical approaches and advice from falls guidelines vary substantially between countries and settings, warranting a standardised approach. At the first World Congress on Falls and Postural Instability in Kuala Lumpur, Malaysia, in December 2019, a worldwide task force of experts in falls in older adults, committed to achieving a global consensus on updating clinical practice guidelines for falls prevention and management by incorporating current and emerging evidence in falls research. Moreover, the importance of taking a person-centred approach and including perspectives from patients, caregivers and other stakeholders was recognised as important components of this endeavour. Finally, the need to specifically include recent developments in e-health was acknowledged, as well as the importance of addressing differences between settings and including developing countries. METHODS a steering committee was assembled and 10 working Groups were created to provide preliminary evidence-based recommendations. A cross-cutting theme on patient's perspective was also created. In addition, a worldwide multidisciplinary group of experts and stakeholders, to review the proposed recommendations and to participate in a Delphi process to achieve consensus for the final recommendations, was brought together. CONCLUSION in this New Horizons article, the global challenges in falls prevention are depicted, the goals of the worldwide task force are summarised and the conceptual framework for development of a global falls prevention and management guideline is presented.

BACKGROUND The relation of gait quality to real-life mobility among older adults is poorly understood. This study examined the association between gait quality, consisting of step variability, smoothness, regularity, symmetry and gait speed with the Life-Space Assessment (LSA). METHODS In community-dwelling older adults (N=232, age 77.5±6.6, 65% females), gait quality was derived from: a) an instrumented walkway: gait speed, variability and walk-ratio; and b) accelerometer: signal variability, smoothness, regularity, symmetry, and time-frequency spatiotemporal variables during 6-minute walk. In addition to collecting LSA scores, cognitive functioning, walking-confidence, and falls were recorded. Spearman correlations (speed as covariate) and Random Forest Regression were used to assess associations between gait quality and LSA, and Gaussian-mixture modeling (GMM) was used to cluster participants. RESULTS Spearman correlations of ρp=0.11 (signal amplitude variability ML), ρp=0.15, ρp=-0.13 (symmetry AP-V, ML-AP), ρp=0.16 (power V) and ρ=0.26 (speed), all p<0.05 and marginally related, ρp=-0.12 (regularity V), ρp=0.11 (smoothness AP) and ρp=-0.11 (step-time variability), p<0.1 were obtained. The cross-validated Random Forest model indicated good fit LSA prediction error of 17.77; gait and cognition were greater contributors than age and gender. GMM indicated two clusters. Group-1(N=189) had better gait quality than Group-2(N=43): greater smoothness AP (2.94±0.75 vs 2.30±0.71); greater similarity AP-V (0.58±0.13 vs 0.40±0.19); lower regularity V (0.83±0.08 vs 0.87±0.10); greater power V (1.86±0.18 vs 0.97±1.84); greater speed (1.09±0.16 vs 1.00±0.16 m/s); lower step time CoV (3.70±1.09 vs 5.09±2.37) and better LSA (76±18 vs 67±18), padjusted<0.004. CONCLUSIONS Gait quality measures taken in the clinic are associated with real-life mobility in the community.

Owing to its superlative carrier mobility and atomic thinness, graphene exhibits great promise for interconnects in future nanoelectronic integrated circuits. Chemical vapor deposition (CVD), the most popular method for wafer-scale growth of graphene, produces monolayers that are polycrystalline, where misoriented grains are separated by extended grain boundaries (GBs). Theoretical models of GB resistivity focused on small sections of an extended GB, assuming it to be a straight line, and predicted a strong dependence of resistivity on misorientation angle. In contrast, measurements produced values in a much narrower range and without a pronounced angle dependence. Here we study electron transport across rough GBs, which are composed of short straight segments connected together into an extended GB. We found that, due to the zig-zag nature of rough GBs, there always exist a few segments that divide the crystallographic angle between two grains symmetrically and provide a highly conductive path for the current to flow across the GBs. The presence of highly conductive segments produces resistivity between 102 to 104 Ω μm regardless of misorientation angle. An extended GB with large roughness and small correlation length has small resistivity on the order of 103 Ω μm, even for highly mismatched asymmetric GBs. The effective slope of the GB, given by the ratio of roughness and lateral correlation length, is an effective universal quantifier for GB resistivity. Our results demonstrate that the probability of finding conductive segments diminishes in short GBs, which could cause a large variation in the resistivity of narrow ribbons etched from polycrystalline graphene. We also uncover spreading resistance due to the current bending in the grains to flow through the conductive segments of the GB and show that it scales linearly with the grain resistance. Our results will be crucial for designing graphene-based interconnects for future integrated circuits.

The greater the number of devices on a network, the higher load in the network, the more chance of a collision occurring, and the longer it takes to transmit a message. The size of load can be identified by measuring the network occupancy, hence it is desirable to minimize the latter. In this paper, we present an approach for network occupancy minimization by optimizing the packing process while satisfying multiple constraints. We formulate the minimization problem as a bin packing problem and we implement a modification of the Best-Fit Decreasing algorithm to find the optimal solution. The approach considers grouping signals that are sent to different destinations in the same package. The analysis is done on a medium-sized plant model, and different topologies are tested. The results show that the proposed solution lowers the network occupancy compared to a reference case.

Abstract Global conservation policy and action have largely neglected protecting and monitoring genetic diversity—one of the three main pillars of biodiversity. Genetic diversity (diversity within species) underlies species’ adaptation and survival, ecosystem resilience, and societal innovation. The low priority given to genetic diversity has largely been due to knowledge gaps in key areas, including the importance of genetic diversity and the trends in genetic diversity change; the perceived high expense and low availability and the scattered nature of genetic data; and complicated concepts and information that are inaccessible to policymakers. However, numerous recent advances in knowledge, technology, databases, practice, and capacity have now set the stage for better integration of genetic diversity in policy instruments and conservation efforts. We review these developments and explore how they can support improved consideration of genetic diversity in global conservation policy commitments and enable countries to monitor, report on, and take action to maintain or restore genetic diversity.

ABSTRACT Introduction The emergence of antimicrobial resistance (AMR) is a threat to public health. In 2015, the World Health Organization (WHO) introduced a global action plan to tackle AMR in the World Health Assembly. Pakistan’s national action plan (NAP) for AMR was released in May 2017 by the Ministry of National Health Services. Based on the NAP, strategies have been initiated on a national and provincial scale in Pakistan. Areas covered This narrative review of the five components of the Pakistan NAP has been undertaken to discuss some of the challenges in implementation of the NAP for AMR in Pakistan including different opinions and views of key stakeholders, combined with suggestions on potential ways to reduce the burden of the AMR. Expert opinion Going forward, healthcare authorities should focus on screening and monitoring of all the objectives of the NAP by establishing proper policies as well as promoting antimicrobial stewardship interventions and Infection prevention and control (IPC) practices. Overall, the comprehensive strengthening of the healthcare system is required to adequately implement the NAP, tackle continued inappropriate antimicrobial use and high AMR rates in Pakistan.

O objetivo do presente estudo foi analisar a associação entre o nível de atividade física e o comportamento sedentário de estudantes de Educação Física de uma faculdade da Zona Oeste do Estado do Rio de Janeiro. Para isso um grupo amostral com 90 estudantes, sendo 56 do sexo masculino e 34 do sexo feminino foi formado por conveniência. Todos os sujeitos responderam ao Questionário Internacional de Atividade Física e foram categorizados como satisfatoriamente ativos ou insatisfatoriamente ativos, bem como, tiveram o relato de seu tempo sentado quantificados representando o comportamento sedentário. Para avaliar a associação entre as distribuições se aplicou o teste do Qui-Quadrado e foi aceito um nível de significância de 5% (p < 0,05). Não foi encontrada associação entre nível de atividade física e comportamento sedentário no grupo amostral (p = 0,408). Conclui-se então, que indivíduos considerados satisfatoriamente ativos não estão necessariamente dentro dos critérios que hipoteticamente exercem proteção no que diz respeito à saúde se for levado em consideração o contraponto que o comportamento sedentário representa sobre tal tela. Ainda, a falta de associação aponta um caminho incongruente no que diz respeito as categorizações do questionário, retratando uma possível fragilidade desse instrumento.

Resumo: Neste artigo se discute as desigualdades de genero nos cursos de engenharia de um campus de uma universidade publica, na perspectiva de discentes de ambos os sexos e pesquisadoras/docentes do sexo feminino. Foram analisados o numero de discentes mulheres ingressos e egressos por curso, o tempo de integralizacao na graduacao, os influenciadores para a escolha da carreira, a discriminacao de genero na academia, o numero de mulheres nos departamentos, a conciliacao entre familia, maternidade e carreira, bem como os obstaculos enfrentados no mercado de trabalho pelo publico feminino.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population. A rare case of cytokine release syndrome in a patient on anti-PD-1 blockade that was likely related to BNT162b2 vaccination supports prospective monitoring of patients with cancer after COVID-19 vaccine administration.

Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology.

Electricity is one of the fundamental necessities of human beings, which has many uses in our day to day life. It is used for different purposes like domestic, industrial and agricultural. The biggest challenge facing electricity distribution is data collection and meter reading. Right now, meter reading is collected manually which give scope for corruption and human error in reading, moreover the wastage of manpower and resources of utility. Prepaid Energy Meter has been implemented in several countries. In fact, the disadvantage of the system is the behavioral control of the users. Moreover, recharging should be carried out on the meter. The problem occurs when consumers leave their premises and electrical pulses are discharged. That's why we need a system to control the electrical pulse wherever they are. In this work, a prepaid energy meter was proposed, implemented and simulated using PROTEUS software. The system was designed using ATmega128 as a microcontroller and GSM technology is advancement over conventional energy meter, which enables consumer to effectively manage their electricity usage. Additionally, it evaluates the accuracy of voltage and current measured by means of this model. Our Suggested model of the prepaid power meter produces the lowest error compared to actual voltage and current. The proposed system replaces traditional meter reading methods and enables remote monitor and control the meter readings regularly not manually. Also, it alerts the consumer when the energy consumption exceeds above the set limit and alerts the utility company if there is any theft that might be happened.