Introdução: O teste Xpert MTB / RIF está sendo cada vez mais utilizado em muitos países como diagnóstico inicial para a tuberculose (TB). Poucos estudos avaliaram o impacto do Xpert no diagnóstico em rotinas de programas de controle de TB no Brasil. O objetivo do presente estudo foi avaliar o impacto da introdução do Xpert MTB / RIF no diagnóstico de TB em uma cidade com alta incidência de TB no Brasil. Métodos: Incluímos pacientes avaliados com testes diagnósticos convencionais durante um ano antes da introdução do Xpert (grupo pré-Xpert) e pacientes avaliados usando Xpert durante um ano após a introdução do teste (grupo pós-Xpert). Resultados: 620 pacientes preencheram os critérios de inclusão (208 no grupo pré-Xpert e 412 no grupo pós-Xpert) e foram incluídos na análise. O tempo até o diagnóstico de TB foi menor no grupo pós-Xpert (0,7 dias, IQR: 0,5-1,0 dias) do que no grupo pré-Xpert (2,0 dias, IQR: 2,0-2,0 dias) (p <0,0001). Características atípicas da doença, como menor perda de peso, febre, dispneia, sudorese noturna e hemoptise; baciloscopia de escarro negativa; cultura negativa e radiografia de tórax atípica de TB foram mais comuns no grupo pós-Xpert do que no grupo pré-Xpert (p <0,0001 para todos). Conclusões: Observamos que a implementação do ensaio Xpert MTB / RIF, em rotinas de programas de controle de TB, melhora e facilita o diagnóstico de tuberculose, especialmente nos casos com manifestações da doença atípica. Esses resultados podem provavelmente ser generalizados para locais com incidência de TB similar. / Introduction: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during inflammation and infection. The interaction between AGEs and RAGE on the plasma membrane causes oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate plasma levels of AGEs and its soluble receptor (sRAGE) in patients with active TB and healthy controls, and to investigate their relationship with food intake and nutritional status. Methods: Case-control study. AGE (carboxymethil lysine, CML) and RAGE were measured by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. Results: 35 TB patients and 35 controls were included in the study. The mean S-RAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0, p=0.046). Among cases that were current smokers, lower S-RAGE levels were associated with mortality (S-RAGE levels= 58.0 ± 36.5 [non-survivors] vs 71.3 ± 25.6 [survivors], p=0.006), and with weight loss (S-RAGE levels= 65.6 ± 27.4 [weight loss] vs 98.6 ± 16.7 [no weight loss], p=0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases than in controls, but there was no correlation between nutritional parameters and CML or S-RAGE levels. Conclusions: TB patients had higher S-RAGE levels than controls. S-RAGE may play a role in disease manifestations and outcomes, being associated with weight loss and mortality.

Introdução: O teste Xpert MTB / RIF está sendo cada vez mais utilizado em muitos países como diagnóstico inicial para a tuberculose (TB). Poucos estudos avaliaram o impacto do Xpert no diagnóstico em rotinas de programas de controle de TB no Brasil. O objetivo do presente estudo foi avaliar o impacto da introdução do Xpert MTB / RIF no diagnóstico de TB em uma cidade com alta incidência de TB no Brasil. Métodos: Incluímos pacientes avaliados com testes diagnósticos convencionais durante um ano antes da introdução do Xpert (grupo pré-Xpert) e pacientes avaliados usando Xpert durante um ano após a introdução do teste (grupo pós-Xpert). Resultados: 620 pacientes preencheram os critérios de inclusão (208 no grupo pré-Xpert e 412 no grupo pós-Xpert) e foram incluídos na análise. O tempo até o diagnóstico de TB foi menor no grupo pós-Xpert (0,7 dias, IQR: 0,5-1,0 dias) do que no grupo pré-Xpert (2,0 dias, IQR: 2,0-2,0 dias) (p <0,0001). Características atípicas da doença, como menor perda de peso, febre, dispneia, sudorese noturna e hemoptise; baciloscopia de escarro negativa; cultura negativa e radiografia de tórax atípica de TB foram mais comuns no grupo pós-Xpert do que no grupo pré-Xpert (p <0,0001 para todos). Conclusões: Observamos que a implementação do ensaio Xpert MTB / RIF, em rotinas de programas de controle de TB, melhora e facilita o diagnóstico de tuberculose, especialmente nos casos com manifestações da doença atípica. Esses resultados podem provavelmente ser generalizados para locais com incidência de TB similar. / Introduction: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during inflammation and infection. The interaction between AGEs and RAGE on the plasma membrane causes oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate plasma levels of AGEs and its soluble receptor (sRAGE) in patients with active TB and healthy controls, and to investigate their relationship with food intake and nutritional status. Methods: Case-control study. AGE (carboxymethil lysine, CML) and RAGE were measured by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. Results: 35 TB patients and 35 controls were included in the study. The mean S-RAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0, p=0.046). Among cases that were current smokers, lower S-RAGE levels were associated with mortality (S-RAGE levels= 58.0 ± 36.5 [non-survivors] vs 71.3 ± 25.6 [survivors], p=0.006), and with weight loss (S-RAGE levels= 65.6 ± 27.4 [weight loss] vs 98.6 ± 16.7 [no weight loss], p=0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases than in controls, but there was no correlation between nutritional parameters and CML or S-RAGE levels. Conclusions: TB patients had higher S-RAGE levels than controls. S-RAGE may play a role in disease manifestations and outcomes, being associated with weight loss and mortality.

Tuberculosis (TB) is primarily a pulmonary disease caused by Mycobacterium tuberculosis (Mtb). Mtb is highly infectious, but studies have shown that only 5–15% of Mtb-infected individuals develop TB disease. The Bacille Calmette-Gu.rin (BCG) vaccine is the only commercially available Mtb vaccine, but its efficacy varies based on the strain used. The Mtb PhoPR-mutant variant, MTBVAC, has been tested as a possible attenuated live vaccine against Mtb. Although it has successfully conferred durable CD4+ T-cell responses in infants, it has also resulted in adverse effects. Our goal is to identify PhoPR-regulated gene(s) that mediate Mtb-induced burst size necrosis in infected cells. PhoPR is a two-component system in mycobacteria. PhoR responds to environmental cues, such as changes in pH, and phosphorylates the PhoP transcription factor, which then activates or suppresses the expression of approximately 40 Mtb genes. The Mtb PhoPR-mutant strain is able to replicate in infected macrophages, but it does not induce the horizontal spread of Mtb to other immune cells. Our lab has previously shown that virulent, cytopathic strains of Mtb, such as H37Rv, suppress early apoptosis, have faster replication rates in macrophages, and trigger cell death at a lethal load threshold of approximately 25 bacteria. Cell death of infected macrophages primarily occurs via necrosis, which involves nuclear pyknosis without DNA fragmentation and general disruption of lipid bilayer membranes. Viable bacilli are released to infect other macrophages and neutrophils recruited to the developing TB lesion. Here, we show that PhoP contributes to burst size necrosis in macrophages and that the PhoP-regulated genes, fadD21 and pks3, are potential drivers of this necrosis. FadD21 and pks3 are involved in the generation of diacyl trehalose/penta-acyl trehalose (DAT/PAT) for cell wall synthesis, suggesting that Mtb cell wall composition may determine virulence. Therefore, we have uncovered potential targets for early intervention or vaccinations to avoid granuloma formation or tissue damage in response to Mtb-induced macrophage necrosis.

M. tuberculosis (Mtb) senses and responds to changes in its environment primar-ily through two-component signalling systems (TCSs). Each TCS contains a trans-membrane histidine kinase (HK ) protein and a cytoplasmic response regulator (RR) protein. HK detects a stimulus and gets phosphorylated. It then binds and transfers the phosphoryl group to the RR of the same TCS. Activated RR then triggers gene ex-pression, including upregulation of the HK and RR involved, eliciting responses that are essential for the bacterium to adapt. Though di erent TCSs detect distinct stimuli, the binding regions of the HK s and RRs share signi cant similarity. This raises the possibil-ity of crosstalk, where HK s dissipate signals to RRs that do not belong to the same TCS. Studies have argued that such dissipation of signals impairs the fitness of the organism, as it decreases the output levels as well as triggers unwanted responses. In contrast, a recent experimental study has discovered that TCSs of Mtb share extensive crosstalk, violating the widely accepted specificity paradigm. In this study, we have attempted to unravel the evolutionary underpinnings of this extensive crosstalk observed in Mtb. We hypothesised that such crosstalk may be advantageous in programmed environments, where there are well-defined sequences of stimuli. In such situations, crosstalk can up-regulate HK s and RRs of non-cognate TCSs. This up-regulation primes the latter TCSs for upcoming signals, increasing their sensitivity. We constructed a mechanistic model of the functioning of TCSs and a fitness variable to qualitatively measure the response of a TCS to a signal, to test the hypothesis. We performed population genetics simulations of the evolution of phenotypes of different crosstalk patterns. We found that in a random environment, the phenotype without any crosstalk is selected over time, which is in agreement with prevalent arguments in favour of specificity of TCSs. But when the environment is programmed, the phenotype with a crosstalk pattern mirroring the pattern of stimuli dominates the population. Finally, we found evidence for the evolutionary preference to preserve crosstalk in gene sequences of HK s and RRs encoded in Mtb. We found that the binding domains of HK s and RRs, which were predicted to share crosstalk, are under greater pressure to be similar than those domains which do not crosstalk. Our study thus provides a plausible explanation of the unexpected presence of crosstalk in Mtb. Since these cross-interactions aid the pathogen to adapt in the host, inhibitors of such interactions are likely to have therapeutic potential.

Mycobacterium tuberculosis (Mtb) is the pathogen that causes Tuberculosis (TB) and is responsible for an average of 1.5 million deaths annually. Although a treatment regimen does exist, Multi-Drug Resistant (MDR-TB) and eXtremely Drug Resistant (XDR-TB) TB strains are becoming a more prevalent concern partly due to failure of patient compliance with the current six to nine month drug treatment regimen. The current diagnostic methods are not able to identify these MDR and XDR-TB strains efficiently therefore more effective point-of-care (POC) diagnostics and drug susceptibility testing (DST) are urgently needed to detect drug resistance and facilitate prompt, appropriate treatment plans. In order to detect TB and efficiently identify drug resistance, this project seeks to develop a novel diagnostic technology based on deoxyribozyme (DNAzyme) sensors. The overall goal of this project is to create an assay which combines Polymerase Chain Reaction (PCR) and DNAzymes to identify drug resistance conferring Single Nucleotide Polymorphisms (SNPs). To safely test the ability of DNAzyme sensors to detect SNPs indicative of multi-drug resistant TB, we have constructed a panel of drug resistant (drugR) nonpathogenic M. bovis BCG. We have designed a multiplex PCR that amplifies 6 chromosomal regions of the genome necessary for the species specific detection of TB and determination of a drug susceptibility profile based on the presence of SNPs. To improve the sensitivity and selectivity of the detection and DST of Mtb, we have designed and optimized DNAzyme sensor assays combined with multiplex PCR analytes that will enable the rapid, POC detection of drug resistance. This work aims to develop novel tools for the prompt and specific diagnosis of TB allowing for the implementation of an iv effective treatment regimen that will ultimately lessen transmission and control the emerging global threat of MDR and XDR-TB.

Background: Tuberculosis (TB) is a major global health threat that results not only in health consequences but also economic consequences. Since 2015 the World Health Organization (WHO) has developed a strategy with the aim of ending the global burden of TB by reducing TB-related deaths, reducing TB incidence, and eliminating the burden of TB-related catastrophic costs for patients and their families. In order to reach these targets, we need to implement effective TB diagnostic and care strategies that are feasible for both patients as well as the health care system. -- Methods: This study consists of two manuscripts which assess the economic burden of TB - one from the patient perspective and the other from the health system perspective. The first manuscript is a systematic review aimed to determine the costs incurred by patients and their households while receiving TB care with direct (medical and non-medical) as well as indirect costs being examined for the pre-diagnostic, post-diagnostic and total phase of care. It analyzed studies with varying patient populations from low-, middle-, and high-income settings to help estimate key factors that drive patient costs. Furthermore, it assessed the proportion of patients that incurred catastrophic costs and the coping strategies that they resorted to in order to offset the costs of TB care. The second manuscript is a modelling study which aimed to develop, parameterize and analyze a decision analytic model to determine the cost, health outcomes as measured by disability-adjusted life years (DALYs) averted and the cost-effectiveness of second-generation lateral flow lipoarabinomannan assay (SG LF-LAM) diagnostic algorithms in people living with HIV (PLHIV) per DALY averted. This model examined four different strategies - 1) the standard of care (SOC) Gene Xpert MTB/RIF only, 2) Gene Xpert MTB/RIF plus LF-LAM for all patients, 3) Gene Xpert MTB/RIF plus LF-LAM for patients with a negative Xpert result, and 4) Gene Xpert MTB/RIF plus LF-LAM for patients who are symptom negative. -- Results: A systematic review showed that total patient costs related to TB care ranged from a mean of $2.80 to $19,153.80 (2019 USD) with costs largely dependent on geographic location as well as patient population, Direct medical and indirect cost components were the largest source of costs for patients and their families while receiving TB care. Direct medical costs included the cost of medication, consultations, diagnostics, follow-up testing, and hospitalization while indirect costs mainly consisted of loss of income. The costs of TB care were considered catastrophic for the majority of patients resulting in them using coping strategies to offset the burden of costs. In the second manuscript, the cost-effectiveness analysis Xpert only was found to be dominated by Xpert + FujiLAM conditional on a negative Xpert with an ICER of 1,000 USD/per DALY averted compared to the standard of care (SOC) Xpert only. Sensitivity analysis found that variations in the key model parameters had an impact on the cost and effectiveness calculations obtained through the model. -- Conclusions: The burden of TB-related costs impact both patients and the health care system at all stages of TB care. Novel diagnostic strategies like the inclusion of FujiLAM for TB diagnosis in PLHIV are cost-effective tools that can aid in case detection and reduce severe outcomes of TB. In order to reduce the TB burden and achieve the "End TB" strategy goals, studies need to work to understand the key components involved in these costs as well as work to develop and implement effective, feasible interventions for TB diagnostics and care.

Corporate social responsibility has evolved as a business strategy, but the business worth of voluntary social conduct has not been well understood. The contradictory research findings mean that social performance is not maximized, which constrains economic growth and sustainable development. Grounded by stakeholder theory, this correlational study was aimed at examining the effect of social responsibility factors on the market-based Fama-French cost of capital. Within a sample of 71 United States banks, the publicly available ethical ratings, financial data, and stock market data were analyzed using multiple regression models. Contrary to the positive effect of social conduct on financial performance common in the literature, this study revealed no significant effect of social factors on the accounting returns, and, consequently, the shareholders perceived the social activities as risky and therefore demanded higher returns. The study also showed that governance, diversity, and employee relation were positively related to accounting returns while product and community factors were negatively related to profits. The implied higher cost of raising equity finance following engagement in social activities is a lesson for corporate managers to exercise caution in their social conduct and carry the investors along. Such inclusive policy could help to minimize investor bias and moderate their consequential adverse reactions to well-intentioned corporate actions. This research contributes to positive social change by assisting the bank managers, directors, investors, regulators, and government in improving the discharge of their respective roles to ensure optimal allocation of resources to competing social activities in a manner that may maximize performance and improve the overall stakeholder wellbeing.

This thesis investigates whether IFRS adoption has led to an increase in the relevance of accounting information for investment decisions. Furthermore, the effects of IFRS are implicitly compared across accounting traditions. As such,  the effects of IFRS on the “quality” of financial reporting are measured based on the cases of listed firms in Germany and listed firms in the UK. This study approaches the effects of IFRS on the quality of financial reporting from two angles. First a review of the academic literature is done to determine whether there has been a general consensus about the effects of IFRS adoption on financial reporting of listed firms in Germany and the UK. As a result of this literature study, a number of propositions are deduced about the effects of IFRS. Subsequently, the investigation of the effects of IFRS takes a statistical perspective. Financial and accounting data are obtained for two samples, one of German listed firms and another of UK listed firms. A number of empirical models are used to determine the quality of financial reporting, including the earnings-returns association (Lev ,1989; Lev &amp; Zarowin, 1999), asymmetric sensitivity of earnings and asymmetric persistence of earnings (Basu, 1997), and the market-to-book ratios (Roychowdhury &amp; Watts, 2003). Additionally, a new tool is introduced for a joint interpretation of the econometric test results, leading potentially to a new method of financial report analysis under dynamic regulatory conditions. Significant statistical evidence is found suggesting a drastic reduction (to the point of complete elimination) in income smoothing in Germany corresponding to the transition from the German national GAAP to IFRS. Additionally, with the introduction of IFRS, the information content of accounting earnings in German firms appears to have increased substantially, while market-to-book ratios have converged towards “1”. On the other hand, the introduction of IFRS in the UK corresponds to statistical evidence consistent with a shift from asymmetric timeliness of earnings under UK GAAP to a significant downward bias in earnings under IFRS. The study also shows significant inter-industry differences in the effects of IFRS that suggest that the inconsistencies in the results of previous studies may have been due to the significant noise created by diverse samples, or due to biased industry representations in the data.

Picturing an interesting combination of extreme sport and spa services in purpose of supporting travel trade in Czech city of Marianske Lazne. Taking advantage of unique layout of Czech's youngest significant spa town and its easy accessibility of diverse services on a relatively small area. Researching problems of public goods and active participation in developing potencial of local ski resort.

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