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The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities.

The promise of the antisense approach to treat a variety of diseases with oligonucleotides and solutions to challenges that have been encountered in their development is attributable to chemical modification of the nucleic acid scaffold. Herein, we describe preliminary data regarding the synthesis of a novel C5-propynyl-β-d-arabinouridine (araU

Background Few data about predictors and outcomes associated with prolonged SARS-CoV-2 RNA shedding (VS) are available. Methods Retrospective study including all patients admitted with COVID-19 in an Italian reference hospital for infectious diseases between March 1 and July 1, 2020. Predictors of viral clearance (VC) and prolonged VS from upper respiratory tract were assessed by Poisson regression and logistic regression analyses. The causal relation between duration of VS and probability of clinical outcomes was evaluated through inverse probability weighted Cox model. Results 536 subjects were included. Median duration of VS from symptoms onset was 18 days (IQR 12-26). The estimated 30-day probability of VC was 70.2% (95%CI:65-75). At multivariable analysis, patients with comorbidities (aIRR = 0.88, p = 0.004), lymphopenia at hospital admission (aIRR = 0.75, p = 0.032) and with moderate/severe respiratory disease (aIRR = 0.42, p 1000 ng/mL at admission (aOR = 1.76, p = 0.035) independently predicted prolonged VS. The achievement of VC doubled the chance of clinical recovery (aHR = 2.17, p

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy. The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia. Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death). A total of 449 patients were included: 39% female, median age 63 (IQR, 50–77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95% CI 3.2–26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7–15.9) in those exposed to pLMWH; p-value = 0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95% CI 0.51–3.79) for patients with an admission PaO2/FiO2 ≤ 300 mmHg and 0.27 (0.03–2.18) for those with PaO2/FiO2 > 300 mmHg; p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). One prominent feature of affected brain regions are iron-loaded microglia, but how iron overload influences microglia physiology and disease response is poorly understood. Here we show that microglia are highly susceptible to ferroptosis, an iron-dependent form of cell death. In a tri-culture of human iPSC-derived neurons, astrocytes, and microglia, under ferroptosis-inducing conditions, microglia undergo a drastic shift in cell state, with increased ferritin levels, disrupted glutathione homeostasis, and altered cytokine signaling. Similar ferroptosis-associated signature (FAS) microglia were uncovered in PD, and the signature was also found in a large cohort of PD patient blood samples, raising the possibility that ferroptosis can be identified clinically. We performed a genome-wide CRISPR screen which revealed a novel regulator of ferroptosis, the vesicle trafficking gene SEC24B. A small molecule screen also nominated several candidates which blocked ferroptosis, some of which are already in clinical use. These data suggest that ferroptosis sits at the interface of cell death and inflammation, and inhibition of this process in microglia and other brain cells may provide new ways for treating neurodegenerative disease.

Aims This study aims to cast light on immunocytometric alterations in COVID-19, a potentially fatal viral infection with heterogeneous clinical expression and a not completely defined pathophysiology. Methods We studied 35 COVID patients at hospital admission testing by cytofluorimetry a large panel of lymphocyte subpopulations and serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A and the soluble receptor of IL-17A (IL-17RA). Key findings At hospital admission, total lymphocytes and most T and B subpopulations were reduced in 50–80% of patients, with close relationship to disease severity. While activated T helper 1 (TH1) and TH17 cells resulted normal or higher. Serum IL-6 was increased in all patients, while TNF-α and IL-17A were higher in advanced stages. A patient subset with low severity had very high IL-17RA levels. Tocilizumab treatment caused an increase of IL-17A in 3/6 patients and a reduction in 3 others, while the lymphocyte number increased in 3 patients and did not change in the others. Significance Cytofluorimetry revealed a functional exhaustion of most lymphocyte populations in COVID patients not involving activated TH1 and TH17. Consequently, there was a relevant cytokines production that contributes to impair the respiratory inflammation. The increase of TH17 and IL-17 in a subset of cases and the evidence of a significant increase of IL-17RA (that prevents the interaction of IL-17 with the cell receptor) in patients with low severity suggest that some patients could benefit from monoclonal antibodies treatment targeting IL-17 pathway. Immunocytofluorimetric markers may contribute to a personalized therapy in COVID patients., Highlights • Total lymphocytes and most T and B sub-clusters were reduced in COVID-19 patients. • Activated TH1 and TH17 cells resulted normal or higher in COVID-19 patients. • Serum IL-6 levels were increased in all patients. • Serum TNF-α and IL-17A were higher in advanced stages. • Evidence of a significant increase of serum IL-17RA in patients with low severity.

Modern field-programmable gate arrays (FPGAs) provide a vast amount of logic resources that can be used to implement complex systems while providing the flexibility to modify the design once deployed. This makes them attractive for software-defined networks (SDNs) applications, and, in fact, most vendors provide the building blocks needed for those applications, which include basic packet classification functions such as exact match, longest prefix match, and match with wildcards. Those are needed for different functions such as routing, security filtering, monitoring or quality of service. The match with wildcards can be done using ternary content addressable memories (TCAMs). TCAMs can be implemented as independent standalone devices or as Internet Protocol (IP) blocks that are used inside networking application-specific integrated circuits (ASICs) such as switching ICs. In both cases, the cells of a TCAM are more complex than that of a normal memory and also than that of a binary content addressable memory (CAMs). This is due to the more complex matching that they need to implement. As FPGAs are used in many different applications, it does not make sense to include TCAM blocks inside them as they would be used only in a small fraction of the systems. Therefore, TCAMs are emulated using the logic resources available inside the FPGA. In recent years, a number of schemes to emulate TCAMs on FPGAs have been proposed, some of them based on the use of the logic resources and others on the use of the embedded memory blocks available on the FPGA. In this brief, a technique to efficiently emulate TCAMs on Xilinx FPGAs is presented. The proposed scheme is based on the use of lookup tables (LUTs) and partial reconfiguration to achieve a more effective use of the FPGA resources while supporting the addition and removal of rules. The proposed scheme has been compared to existing implementations and the results show that it can achieve significant savings in resource usage. In addition, it enables the use of all the LUTs in the device for TCAM implementation, something that is not supported by existing approaches that use LUTRAMs.

Esta investigación tiene como objetivo principal determinar los efectos que provoca el etiquetado chileno de alimentos (Ley N° 20.606 vigencia en Chile desde el año 2016) sobre el uso de información nutricional, mediante técnicas experimentales, con el fin de calificar la calidad de decisión que realiza el consumidor en base a los estímulos de etiquetado nutricional. El cuestionario aplicado se apoya en la investigación realizada por Christine Moorman (1990) que explica el Proceso de Utilización de Información Nutricional. En base a cuatro escenarios distintos se realiza un análisis intesujetos aplicando el Modelo Lineal Multivariante que dispone la herramienta SPSS en una muestra de 200 encuestados. Los principales resultados apuntan a que el actual etiquetado de los envases de galletas, donde se disponen de sellos de advertencia y guías diarias de alimentación simultáneas, representan el escenario donde se toman las decisiones de mayor calidad. Motivación duradera y orientación preventiva son algunas de las características del consumidor que afectan la toma de decisión. El género no influye en la calidad de decisión.

Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a wellknown molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia. Methods: Rats were subjected to transient global ischemia by the 4-vessel occlusion or sham operation. The animals were sacrificed at 24 hours, 48 hours, and 7 days after ischemia. The hippocampal CA1 was microdissected and processed to examine mRNA and protein level. To assess neuronal death, tissue sections were cut and processed for Fluoro-Jade and Nissl staining. Results: Here we show that ischemic insults increase abundance of Gadd45b and brain-derived neurotrophic factor, a known target of Gadd45 mediated demethylation, in selectively-vulnerable hippocampal CA1 neurons. We further show that knockdown of Gadd45b increases abundance of a pro-apoptotic Bcl-2 family member Bax while decreasing the antiapoptotic protein Bcl-2, which together promote neuronal death. Conclusions: These findings document a protective role of Gadd45b against neuronal insults associated with global ischemia and identify Gadd45b as a potential therapeutic target for the amelioration of hippocampal neurodegeneration.

OBJECTIVES: No study evaluated the contribution of adjunctive surgery in bedaquiline-treated patients. This study describes treatment outcomes and complications in a cohort of drug-resistant pulmonary tuberculosis (TB) cases treated with bedaquiline-containing regimens undergoing surgery.METHODS: This retrospective observational study recruited patients treated for TB in 12 centres in 9 countries between January 2007 and March 2015. Patients who had surgical indications in a bedaquiline-treated programme-based cohort were selected and surgery-related information was collected. Patient characteristics and surgical indications were described together with type of operation, surgical complications, bacteriological conversion rates, and treatment outcomes. Treatment outcomes were evaluated according to the time of surgery.RESULTS: 57 bedaquiline-exposed cases resistant to a median of 7 drugs had indication for surgery (52 retreatments; 50 extensively drug-resistant (XDR) or pre XDR-TB). Sixty percent of cases initiated bedaquiline treatment following surgery, while 36.4% underwent the bedaquiline regimen before surgery and completed it after the operation. At treatment completion 90% culture-converted with 69.1% achieving treatment success; 21.8% had unfavourable outcomes (20.0% treatment failure, 1.8% lost to follow-up), and 9.1% were still undergoing treatment.CONCLUSIONS: The study results suggest that bedaquiline and surgery can be safely and effectively combined in selected cases with a specific indication.

Fluxonorm® is a dietary supplement that includes water-soluble extracts of Solidago virga-aurea, Phyllantus niruri, Epilobium angustifolium, Peumus boldus and Ononis spinosa. The aim of the present study was to evaluate the tolerability and efficacy of Fluxonorm® in improving lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH) in combination with standard of care.Lower urinary tract symptoms can be improved by a marked anti-inflammatory action on the lower urinary tract (irritative symptoms) and/or by an anti-proliferative action (obstructive symptoms) on the prostate. Thirty patients were enrolled to evaluate the effect of Fluxonorm® on improving lower urinary tract symptoms. All patients complained of lower urinary tract symptoms (LUTS), such as hesitancy, poor flow, intermittent flow, incomplete voiding (obstructive symptoms), as well as increased frequency, nocturia and urgency (storage symptoms). All patients were treated with one tablet of Fluxonorm® (1200 mg) daily for 30 days to corroborate the results of our observation in which the food supplement (800 µg/mL) was also studied on the human prostate cancer PC3 cell line (antiproliferative activity) and on prostaglandin (PG)E2 production (anti-inflammatory activity). In addition, the effect of this compound on cyclooxygenase-2 (COX-2) gene expression was investigated. Finally, a bioinformatic analysis was conducted with the aim of unravelling the mechanism of action underlying the observed bio-pharmacological effects.As hypothesized in our preclinical research, adding Fluxonorm® to the therapy of enrolled patients improved all studied clinical parameters, including maximum flow (Qmax), after one month of treatment. In the preclinical evaluation, this formulation reduced PC3 cell viability and PGE2 production. The effects were also paralleled by reduced COX-2 gene expression and Fluxonorm®'s partly related content of catechin. While docking studies pointed out to the putative inhibition of matrix metalloproteinse-2 by gallic acid, as a further mechanism underlying the observed anti-proliferative effects, in PC3 cells exposed to Fluxonorm®.Fluxonorm® improved the efficacy of standard therapy, in terms of antioxidant/anti-inflammatory effects, for the management of lower urinary tract symptoms (LUTS). This could be related, albeit partially, to the blunting effect of this compound on PGE2 production.

A recurring task in security monitoring consists in finding scan-type flows, namely flows which exhibit a large cardinality in terms of number of distinct source/destination addresses, or in most generality packet-level identifiers (e.g. ports, header fields, etc). But cardinality estimation requires to “remember” the identifiers seen in the past, and becomes quite challenging when the goal is to implement per-flow distinct count at wire speed, while maintaining high processing throughput and limited memory footprint. In this demo, we will show how to use HyperLogLog sketches to implement an efficient and innovative top-k cardinality estimation algorithm, called FlowFight. The algorithm has been tested and integrated in a full-fledged software router such as Vector Packet Processor.

Bloom filters and cuckoo filters are used in many applications to reduce the amount of memory needed to check if an element belongs to a set. The main drawback of these filters is that with low probability, a positive is returned for an element that is not in the set. Recently, the concept of Bloom filters with a false positive free zone has been introduced showing that false positives can be avoided when the universe from which elements are taken and the number of elements inserted in the filter are both small. Unfortunately, this limits the use of such false positive free Bloom filters in many practical applications. In this paper, a false positive free, i.e. perfect, cuckoo filter is presented and evaluated. The proposed design supports universe sizes of billions of elements and stores millions of elements, making it practical for a wide range of applications. The perfect cuckoo filter can be also used to perform mapping, further extending the range of scenarios in which can be used. The benefits of the proposed perfect cuckoo filter are illustrated with two case studies: IP address blacklisting and longest prefix match for IP forwarding.

In 2015, #FeesMustFall, the largest student movement since the end of the apartheid regime, united with outsourced university workers, in reaction to the neoliberal trajectory of the South Africa higher education system. Based on data collected through extended participant observation and interviews, this chapter analyzes the process of solidarity that emerged between students and workers at the University of Johannesburg and investigates how their unity in action achieved the partial removal of outsourcing labor relations. The processes of solidarity that emerged, drawing from the progressive aspects of a historically determined senso comune, had the potential to question the whole post-apartheid societal structure, obliging the state and the universities’ management to concede remarkable concessions in order to disarticulate this solidarity. This analysis contributes to the debate about limits and potentialities of student and worker movements and their capacity to question the status quo and imagine decolonial alternatives.