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Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be serious when contracted during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is associated with the tachyzoite form that spreads rapidly within the host. However, under stress conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the central nervous system, retina and muscle. Because this latent form of the parasite is resistant to all currently available treatments, and is central to persistence and transmission of the parasite, specific therapeutic strategies targeting this developmental stage need to be found. T. gondii contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing drug target because it is essential for tachyzoite viability and contains several key metabolic pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is unknown. Our objective was thus to study the contribution of the apicoplast to the viability and persistence of bradyzoites during chronic toxoplasmosis. We have used complementary strategies based on stage-specific promoters to generate conditional bradyzoite mutants of essential apicoplast genes. Our results show that specifically targeting the apicoplast in both in vitro or in vivo-differentiated bradyzoites leads to a loss of long-term bradyzoite viability, highlighting the importance of this organelle for this developmental stage. This validates the apicoplast as a potential area to look for therapeutic targets in bradyzoites, with the aim to interfere with this currently incurable parasite stage.
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Apicoplastos , Cistos , Toxoplasma , Toxoplasmose , Animais , Feminino , Gravidez , Humanos , Toxoplasma/genética , Sistema Nervoso Central , MamíferosRESUMO
Throughout the SARS-CoV-2 pandemic, limited diagnostic capacities prevented sentinel testing, demonstrating the need for novel testing infrastructures. Here, we describe the setup of a cost-effective platform that can be employed in a high-throughput manner, which allows surveillance testing as an acute pandemic control and preparedness tool, exemplified by SARS-CoV-2 diagnostics in an academic environment. The strategy involves self-sampling based on gargling saline, pseudonymized sample handling, automated RNA extraction, and viral RNA detection using a semiquantitative multiplexed colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay with an analytical sensitivity comparable with RT-qPCR. We provide standard operating procedures and an integrated software solution for all workflows, including sample logistics, analysis by colorimetry or sequencing, and communication of results. We evaluated factors affecting the viral load and the stability of gargling samples as well as the diagnostic sensitivity of the RT-LAMP assay. In parallel, we estimated the economic costs of setting up and running the test station. We performed > 35,000 tests, with an average turnover time of < 6 h from sample arrival to result announcement. Altogether, our work provides a blueprint for fast, sensitive, scalable, cost- and labor-efficient RT-LAMP diagnostics, which is independent of potentially limiting clinical diagnostics supply chains.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Pandemias/prevenção & controle , Sensibilidade e Especificidade , RNA Viral/genéticaRESUMO
Shift workers have a 25 to 40% higher risk of depression and anxiety partly due to a misalignment between the central circadian clock and daily environmental/behavioral cycles that may negatively affect mood and emotional well-being. Hence, evidence-based circadian interventions are required to prevent mood vulnerability in shift work settings. We used a stringently controlled 14-d circadian paradigm to assess mood vulnerability during simulated night work with either daytime and nighttime or daytime-only eating as compared with simulated day work (baseline). Simulated night work with daytime and nighttime eating increased depression-like mood levels by 26.2% (p-value adjusted using False Discovery Rates, pFDR = 0.001; effect-size r = 0.78) and anxiety-like mood levels by 16.1% (pFDR = 0.001; effect-size r = 0.47) compared to baseline, whereas this did not occur with simulated night work in the daytime-only eating group. Importantly, a larger degree of internal circadian misalignment was robustly associated with more depression-like (r = 0.77; P = 0.001) and anxiety-like (r = 0.67; P = 0.002) mood levels during simulated night work. These findings offer a proof-of-concept demonstration of an evidence-based meal timing intervention that may prevent mood vulnerability in shift work settings. Future studies are required to establish if changes in meal timing can prevent mood vulnerability in night workers.
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Ansiedade , Relógios Circadianos , Transtorno Depressivo , Refeições , Jornada de Trabalho em Turnos , Tolerância ao Trabalho Programado , Adulto , Ansiedade/prevenção & controle , Ritmo Circadiano , Transtorno Depressivo/prevenção & controle , Feminino , Humanos , Masculino , Refeições/psicologia , Jornada de Trabalho em Turnos/psicologia , Tolerância ao Trabalho Programado/psicologia , Adulto JovemRESUMO
Loss-of-function mutations in the GNAL gene are responsible for DYT-GNAL dystonia. However, how GNAL mutations contribute to synaptic dysfunction is still unclear. The GNAL gene encodes the Gαolf protein, an isoform of stimulatory Gαs enriched in the striatum, with a key role in the regulation of cAMP signaling. Here, we used a combined biochemical and electrophysiological approach to study GPCR-mediated AC-cAMP cascade in the striatum of the heterozygous GNAL (GNAL+/-) rat model. We first analyzed adenosine type 2 (A2AR), and dopamine type 1 (D1R) receptors, which are directly coupled to Gαolf, and observed that the total levels of A2AR were increased, whereas D1R level was unaltered in GNAL+/- rats. In addition, the striatal isoform of adenylyl cyclase (AC5) was reduced, despite unaltered basal cAMP levels. Notably, the protein expression level of dopamine type 2 receptor (D2R), that inhibits the AC5-cAMP signaling pathway, was also reduced, similar to what observed in different DYT-TOR1A dystonia models. Accordingly, in the GNAL+/- rat striatum we found altered levels of the D2R regulatory proteins, RGS9-2, spinophilin, Gß5 and ß-arrestin2, suggesting a downregulation of D2R signaling cascade. Additionally, by analyzing the responses of striatal cholinergic interneurons to D2R activation, we found that the receptor-mediated inhibitory effect is significantly attenuated in GNAL+/- interneurons. Altogether, our findings demonstrate a profound alteration in the A2AR/D2R-AC-cAMP cascade in the striatum of the rat DYT-GNAL dystonia model, and provide a plausible explanation for our previous findings on the loss of dopamine D2R-dependent corticostriatal long-term depression.
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Distonia , Distúrbios Distônicos , Ratos , Animais , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Dopamina/metabolismo , AMP Cíclico/metabolismo , Distonia/genética , Transdução de Sinais/fisiologia , Corpo Estriado/metabolismo , Receptores Dopaminérgicos/metabolismo , Isoformas de Proteínas/metabolismoRESUMO
In Vietnam and the Philippines, viral hepatitis is the leading cause of cirrhosis and liver cancer. This study aims to understand the barriers and enablers of people receiving care for hepatitis B and C to support both countries' efforts to eliminate viral hepatitis as a public health threat by 2030. Retrospective, semi-structured interviews were conducted with a purposive, quota-based sample of 63 people living with hepatitis B or C in one province of Vietnam and one region of the Philippines. A rapid deductive approach to thematic analysis produced key findings among the three phases of care: (1) pre-awareness and testing, (2) linkage and treatment initiation and (3) ongoing treatment and recovery. The research found that participants followed five typical journeys, from a variety of entry points. Barriers during the pre-awareness and testing phase included limited awareness about hepatitis and its management, stigma and psychological impacts. Enablers included being familiar with the health system and/or patients benefiting from social connections within the health systems. During the linkage and treatment initiation phase, barriers included difficult physical access, complex navigation and inadequate counselling. In this phase, family support emerged as a critical enabler. During the ongoing treatment and recovery phase, the cost of care and socially and culturally informed perceptions of the disease and medication use were both barriers and enablers. Exploring peoples' journeys with hepatitis B and C in Vietnam and the Philippines revealed many similarities despite the different cultural and health system contexts. Insights from this study may help generate a contextualized, people-centred evidence base to inform the design and improvement of primary care services for hepatitis in both research sites.
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Acessibilidade aos Serviços de Saúde , Humanos , Vietnã/epidemiologia , Filipinas/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Hepatite B , Entrevistas como Assunto , Adulto Jovem , Hepatite C/epidemiologia , Hepatite C/tratamento farmacológicoRESUMO
INTRODUCTION: Brain cancer is the leading cause of cancer-related deaths in children and the majority of childhood brain tumors are diagnosed without determination of their underlying etiology. Little is known about risk factors for childhood brain tumors in Vietnam. The objective of this case-control study was to identify maternal and perinatal factors associated with brain tumors occurring in young Vietnamese children and adolescents. METHODS: We conducted a hospital-based case-control study at Viet Duc University Hospital in Hanoi, Vietnam. Cases consisted of children with brain tumors aged 0-14 years old admitted to the hospital from January 2020 to July 2022 while the controls were age and sex-matched hospitalized children diagnosed with head trauma. Perinatal characteristics were abstracted from hospital medical records and maternal medical, behavioral, and sociodemographic factors were collected through in-person interviews. Conditional logistic regression models were used to examine maternal and perinatal factors associated with childhood brain tumors. RESULTS: The study sample included 220 children (110 cases and 110 controls) whose average age was 8.9 years and 41.8% were girls. Children born to mothers aged greater than 30 years at the time of the child's birth had a higher risk of childhood brain tumors compared to those born to mothers aged from 18 to 30 years old (OR = 2.55; 95% CI: 1.13-5.75). Additionally low maternal body mass index prior to the current pregnancy of <18.5 kg/m2 significantly increased the odds of having a child with a brain tumor in relation to normal maternal body mass index from 18.5-22.9 kg/m2 (OR = 3.19; 95% CI: 1.36 - 7.50). CONCLUSION: Advanced maternal age and being markedly underweight were associated with an increased odds of having a child with a brain tumor. A population-based study with larger sample size is needed to confirm and extend the present findings.
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Neoplasias Encefálicas , Humanos , Estudos de Casos e Controles , Feminino , Neoplasias Encefálicas/epidemiologia , Vietnã/epidemiologia , Criança , Masculino , Adolescente , Fatores de Risco , Pré-Escolar , Lactente , Adulto , Gravidez , Recém-Nascido , Adulto Jovem , Idade MaternaRESUMO
This paper proposes a surveillance model for plant pests that can optimally allocate resources among survey tools with varying properties. While some survey tools are highly specific for the detection of a single pest species, others are more generalized. There is considerable variation in the cost and sensitivity of these tools, but there are no guidelines or frameworks for identifying which tools are most cost-effective when used in surveillance programs that target the detection of newly invaded populations. To address this gap, we applied our model to design a trapping surveillance program in New Zealand for bark- and wood-boring insects, some of the most serious forest pests worldwide. Our findings show that exclusively utilizing generalized traps (GTs) proves to be highly cost-effective across a wide range of scenarios, particularly when they are capable of capturing all pest species. Implementing surveillance programs that only employ specialized traps (ST) is cost-effective only when these traps can detect highly damaging pests. However, even in such cases, they significantly lag in cost-effectiveness compared to GT-only programs due to their restricted coverage. When both GTs and STs are used in an integrated surveillance program, the total expected cost (TEC) generally diminishes when compared to programs relying on a single type of trap. However, this relative reduction in TEC is only marginally larger than that achieved with GT-only programs, as long as highly damaging species can be detected by GTs. The proportion of STs among the optimal required traps fluctuates based on several factors, including the relative pricing of GTs and STs, pest arrival rates, potential damage, and, more prominently, the coverage capacity of GTs. Our analysis suggests that deploying GTs extensively across landscapes appears to be more cost-effective in areas with either very high or very low levels of relative risk density, potential damage, and arrival rate. Finally, STs are less likely to be required when the pests that are detected by those tools have a higher likelihood of successful eradication because delaying detection becomes less costly for these species.
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Biosseguridade , Insetos , Animais , Florestas , Especificidade da Espécie , Alocação de RecursosRESUMO
African swine fever virus (ASFV) has spread through many countries and regions worldwide, causing significant losses. Timely detection of ASFV-infected pigs is crucial for disease control. In this study, we assessed the performance of two pen-side tests: a portable real-time PCR (qPCR) test for detecting viral genomic DNA and a lateral flow immunoassay (LFIA) for detecting viral antigens. To determine the time from infection to the earliest detection, 10 ASFV-seronegative pigs were inoculated intramuscularly with 104.0 hemadsorption dose 50 of a highly virulent ASFV strain. Whole blood and oral swab samples were alternately collected from each group of five pigs daily until all succumbed to the infection. Samples were promptly subjected to the two pen-side tests upon collection, and a subset was transported to a veterinary diagnostic laboratory for analysis using a reference qPCR assay. Viral genomic DNA was consistently detected by the reference qPCR assay in all blood samples from 2 days postinfection (dpi), preceding the onset of clinical signs, and in oral swabs from 4 dpi onwards. The portable qPCR test demonstrated comparable performance to the reference qPCR assay for both whole blood and oral swab samples. The LFIA exhibited 100% specificity when testing with whole blood samples but showed reduced sensitivity, particularly for blood samples collected early or late after infection. The antigen test did not perform well with oral swabs.
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Vírus da Febre Suína Africana , Febre Suína Africana , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Animais , Vírus da Febre Suína Africana/isolamento & purificação , Vírus da Febre Suína Africana/genética , Febre Suína Africana/diagnóstico , Febre Suína Africana/virologia , Suínos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/veterinária , DNA Viral/genética , Imunoensaio/métodos , Antígenos Virais/análiseRESUMO
BACKGROUND: Recent years have seen a growing interest in the use of digital tools for delivering person-centred mental health care. Experience Sampling Methodology (ESM), a structured diary technique for capturing moment-to-moment variation in experience and behaviour in service users' daily life, reflects a particularly promising avenue for implementing a person-centred approach. While there is evidence on the effectiveness of ESM-based monitoring, uptake in routine mental health care remains limited. The overarching aim of this hybrid effectiveness-implementation study is to investigate, in detail, reach, effectiveness, adoption, implementation, and maintenance as well as contextual factors, processes, and costs of implementing ESM-based monitoring, reporting, and feedback into routine mental health care in four European countries (i.e., Belgium, Germany, Scotland, Slovakia). METHODS: In this hybrid effectiveness-implementation study, a parallel-group, assessor-blind, multi-centre cluster randomized controlled trial (cRCT) will be conducted, combined with a process and economic evaluation. In the cRCT, 24 clinical units (as the cluster and unit of randomization) at eight sites in four European countries will be randomly allocated using an unbalanced 2:1 ratio to one of two conditions: (a) the experimental condition, in which participants receive a Digital Mobile Mental Health intervention (DMMH) and other implementation strategies in addition to treatment as usual (TAU) or (b) the control condition, in which service users are provided with TAU. Outcome data in service users and clinicians will be collected at four time points: at baseline (t0), 2-month post-baseline (t1), 6-month post-baseline (t2), and 12-month post-baseline (t3). The primary outcome will be patient-reported service engagement assessed with the service attachment questionnaire at 2-month post-baseline. The process and economic evaluation will provide in-depth insights into in-vivo context-mechanism-outcome configurations and economic costs of the DMMH and other implementation strategies in routine care, respectively. DISCUSSION: If this trial provides evidence on reach, effectiveness, adoption, implementation and maintenance of implementing ESM-based monitoring, reporting, and feedback, it will form the basis for establishing its public health impact and has significant potential to bridge the research-to-practice gap and contribute to swifter ecological translation of digital innovations to real-world delivery in routine mental health care. TRIAL REGISTRATION: ISRCTN15109760 (ISRCTN registry, date: 03/08/2022).
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Serviços de Saúde Mental , Humanos , Serviços de Saúde Mental/economia , Alemanha , Bélgica , Eslováquia , Transtornos Mentais/terapia , Transtornos Mentais/economia , Avaliação Momentânea Ecológica , Europa (Continente) , Análise Custo-Benefício/métodosRESUMO
BACKGROUND: This study presents guidelines for implementation distilled from the findings of a realist evaluation. The setting was local health districts in New South Wales, Australia that implemented three clinical improvement initiatives as part of a state-wide program. We focussed on implementation strategies designed to develop health professionals' capability to deliver value-based care initiatives for multisite programs. Capability, which increases implementers' ability to cope with unexpected scenarios is key to managing change. METHODS: We used a mixed methods realist evaluation which tested and refined program theories elucidating the complex dynamic between context (C), mechanism (M) and outcome (O) to determine what works, for whom, under what circumstances. Data was drawn from program documents, a realist synthesis, informal discussions with implementation designers, and interviews with 10 key informants (out of 37 identified) from seven sites. Data analysis employed a retroductive approach to interrogate the causal factors identified as contributors to outcomes. RESULTS: CMO statements were refined for four initial program theories: Making it Relevant- where participation in activities was increased when targeted to the needs of the staff; Investment in Quality Improvement- where engagement in capability development was enhanced when it was valued by all levels of the organisation; Turnover and Capability Loss- where the effects of staff turnover were mitigated; and Community-Wide Priority- where there was a strategy of spanning sites. From these data five guiding principles for implementers were distilled: (1) Involve all levels of the health system to effectively implement large-scale capability development, (2) Design capability development activities in a way that supports a learning culture, (3) Plan capability development activities with staff turnover in mind, (4) Increased capability should be distributed across teams to avoid bottlenecks in workflows and the risk of losing key staff, (5) Foster cross-site collaboration to focus effort, reduce variation in practice and promote greater cohesion in patient care. CONCLUSIONS: A key implementation strategy for interventions to standardise high quality practice is development of clinical capability. We illustrate how leadership support, attention to staff turnover patterns, and making activities relevant to current issues, can lead to an emergent learning culture.
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Análise de Dados , Hospitais , Humanos , Austrália , Pessoal de Saúde , Investimentos em SaúdeRESUMO
Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.
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BACKGROUND: Vietnam's primary mechanism of achieving sustainable funding for universal health coverage (UHC) and financial protection has been through its social health insurance (SHI) scheme. Steady progress towards access has been made and by 2020, over 90% of the population were enrolled in SHI. In 2022, as part of a larger transition towards the increased domestic financing of healthcare, tuberculosis (TB) services were integrated into SHI. This change required people with TB to use SHI for treatment at district-level facilities or to pay out of pocket for services. This study was conducted in preparation for this transition. It aimed to understand more about uninsured people with TB, assess the feasibility of enrolling them into SHI, and identify the barriers they faced in this process. METHODS: A mixed-method case study was conducted using a convergent parallel design between November 2018 and January 2022 in ten districts of Hanoi and Ho Chi Minh City, Vietnam. Quantitative data were collected through a pilot intervention that aimed to facilitate SHI enrollment for uninsured individuals with TB. Descriptive statistics were calculated. Qualitative interviews were conducted with 34 participants, who were purposively sampled for maximum variation. Qualitative data were analyzed through an inductive approach and themes were identified through framework analysis. Quantitative and qualitative data sources were triangulated. RESULTS: We attempted to enroll 115 uninsured people with TB into SHI; 76.5% were able to enroll. On average, it took 34.5 days to obtain a SHI card and it cost USD 66 per household. The themes indicated that a lack of knowledge, high costs for annual premiums, and the household-based registration requirement were barriers to SHI enrollment. Participants indicated that alternative enrolment mechanisms and greater procedural flexibility, particularly for undocumented people, is required to achieve full population coverage with SHI in urban centers. CONCLUSIONS: Significant addressable barriers to SHI enrolment for people affected by TB were identified. A quarter of individuals remained unable to enroll after receiving enhanced support due to lack of required documentation. The experience gained during this health financing transition is relevant for other middle-income countries as they address the provision of financial protection for the treatment of infectious diseases.
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Tuberculose , Cobertura Universal do Seguro de Saúde , Humanos , Vietnã , Seguro Saúde , Atenção à Saúde , Tuberculose/terapiaRESUMO
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood-brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
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Ataxina-7 , Dependovirus , Modelos Animais de Doenças , Peptídeos , Fenótipo , RNA Interferente Pequeno , Ataxias Espinocerebelares , Expansão das Repetições de Trinucleotídeos , Animais , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Ataxias Espinocerebelares/metabolismo , Peptídeos/genética , Dependovirus/genética , Camundongos , Ataxina-7/genética , Ataxina-7/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , RNA Interferente Pequeno/genética , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Camundongos Transgênicos , Cerebelo/metabolismo , Cerebelo/patologia , Humanos , Terapia Genética/métodos , AlelosRESUMO
Flavonoids and stilbenoids, crucial secondary metabolites abundant in plants and fungi, display diverse biological and pharmaceutical activities, including potent antioxidant, anti-inflammatory, and antimicrobial effects. However, conventional production methods, such as chemical synthesis and plant extraction, face challenges in sustainability and yield. Hence, there is a notable shift towards biological production using microorganisms like Escherichia coli and yeast. Yet, the drawbacks of using E. coli and yeast as hosts for these compounds persist. For instance, yeast's complex glycosylation profile can lead to intricate protein production scenarios, including hyperglycosylation issues. Consequently, Corynebacterium glutamicum emerges as a promising alternative, given its adaptability and recent advances in metabolic engineering. Although extensively used in biotechnological applications, the potential production of flavonoid and stilbenoid in engineered C. glutamicum remains largely untapped compared to E. coli. This review explores the potential of metabolic engineering in C. glutamicum for biosynthesis, highlighting its versatility as a cell factory and assessing optimization strategies for these pathways. Additionally, various metabolic engineering methods, including genomic editing and biosensors, and cofactor regeneration are evaluated, with a focus on C. glutamicum. Through comprehensive discussion, the review offers insights into future perspectives in production, aiding researchers and industry professionals in the field.
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Corynebacterium glutamicum , Flavonoides , Engenharia Metabólica , Estilbenos , Corynebacterium glutamicum/metabolismo , Corynebacterium glutamicum/genética , Engenharia Metabólica/métodos , Flavonoides/biossíntese , Flavonoides/metabolismo , Estilbenos/metabolismoRESUMO
Interactions of amyloid-ß (Aß) peptides with neuronal membrane are associated with the development of Alzheimer's disease (AD). Ganglioside monosialotetrahexosylganglioside (GM1) lipids have been shown to form clusters that induce the structural conversion of Aß and promote the incorporation of Aß into the membrane via the membrane surface electrical potential. Prior to the onset of AD symptoms, GM1 clusters may not have formed but the concentration of GM1 may have already changed, and our question is whether this early concentration modification affects the structure and mechanical properties of the membrane. Using one model for healthy cell membranes and three models for AD cell membranes, we carry out 2 µs all-atom molecular dynamics simulations for each model to compare the structure and elasticity of the two membrane types. The simulations show that at the physiological concentration, 1%-3%, GM1 does not form clusters. The reduction of the GM1 lipid does not significantly alter the area per lipid, the membrane thickness, and the lipid order parameters of the AD membranes. However, the dipole potential, the bending, and twist moduli are decreased for the AD membranes. We suggest that these changes in the AD membranes are factors that could trigger the interaction and incorporation of Aß to the membranes. Finally, we show that changes in the sphingomyelin lipid concentrations do not affect the membrane structure and elasticity.
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BACKGROUND: Subclinical tuberculosis has been increasingly recognized as a separate state in the spectrum of the disease. However, evidence on the transmissibility of subclinical tuberculosis is still inconclusive. METHODS: We re-analyzed the data from the 2007 combined tuberculosis prevalence and tuberculin surveys in Vietnam. Poisson regression with robust standard errors was conducted to assess the effect of clinical presentation of individuals with tuberculosis in the household on tuberculin skin test (TST) positivity among children aged 6-14 years who participated in the tuberculin survey, adjusting for child's age, smear status of the index patient, and other covariates. RESULTS: In the multivariate analysis, we found significantly increased risks for TST positivity in children living with patients with clinical, smear-positive tuberculosis, compared with those living with individuals without tuberculosis (adjusted risk ratio [aRR]: 3.04; 95% confidence interval [CI]: 2.00-4.63) and with those living with patients with subclinical tuberculosis, adjusting for index smear status (aRR: 2.26; 95% CI: 1.03-4.96). Among children aged 6-10 years, those living with patients with clinical, smear-positive tuberculosis and those living with patients with subclinical, smear-positive tuberculosis had similarly increased risks of TST positivity compared with those living with individuals without tuberculosis (aRRs [95% CI] of 3.56 [1.91-6.62] and 3.11 [1.44-6.72], respectively). CONCLUSIONS: Our findings support the hypothesis that smear-positive subclinical tuberculosis contributes to Mycobacterium tuberculosis transmission. To eliminate tuberculosis in 2035, control strategies need to address subclinical presentations of the disease.
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Mycobacterium tuberculosis , Tuberculose Pulmonar , Tuberculose , Criança , Humanos , Tuberculose Pulmonar/epidemiologia , Tuberculina , Fatores de Risco , Teste Tuberculínico , Tuberculose/epidemiologia , Inquéritos e QuestionáriosRESUMO
To assess sex disparities in tuberculosis in Vietnam, we conducted a nested, case-control study based on a 2017 tuberculosis prevalence survey. We defined the case group as all survey participants with laboratory-confirmed tuberculosis and the control group as a randomly selected group of participants with no tuberculosis. We used structural equation modeling to describe pathways from sex to tuberculosis according to an a priori conceptual framework. Our analysis included 1,319 participants, of whom 250 were case-patients. We found that sex was directly associated with tuberculosis prevalence (adjusted odds ratio for men compared with women 3.0 [95% CI 1.7-5.0]) and indirectly associated through other domains. The strong sex difference in tuberculosis prevalence is explained by a complex interplay of factors relating to behavioral and environmental risks, access to healthcare, and clinical manifestations. However, after controlling for all those factors, a direct sex effect remains that might be caused by biological factors.
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Tuberculose , Humanos , Feminino , Masculino , Vietnã/epidemiologia , Estudos de Casos e Controles , Tuberculose/epidemiologia , Inquéritos e Questionários , PrevalênciaRESUMO
The aim of this study is to analyse the changing patterns in the transmission of COVID-19 in relation to changes in Vietnamese governmental policies, based on epidemiological data and policy actions in a large Vietnamese province, Bac Ninh, in 2021. Data on confirmed cases from January to December 2021 were collected, together with policy documents. There were three distinct periods of the COVID-19 pandemic in Bac Ninh province during 2021. During the first period, referred to as the 'Zero-COVID' period (01/04-07/04/2021), there was a low population vaccination rate, with less than 25% of the population receiving its first vaccine dose. Measures implemented during this period focused on domestic movement restrictions, mask mandates, and screening efforts to control the spread of the virus. The subsequent period, referred to as the 'Transition' period (07/05-10/22/2021), witnessed a significant increase in population vaccination coverage, with 80% of the population receiving their first vaccine dose. During this period, several days passed without any reported COVID-19 cases in the community. The local government implemented measures to manage domestic actions and reduce the time spent in quarantine, and encouraged home quarantining for the close contacts of cases with COVID-19. Finally, the 'New-normal' stage (10/23-12/31/2021), during which the population vaccination coverage with a second vaccine dose increased to 70%, and most of the mandates for the prevention and control of COVID-19 were reduced. In conclusion, this study highlights the importance of governmental policies in managing and controlling the transmission of COVID-19 and provides insights for developing realistic and context-specific strategies in similar settings.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Quarentena , SARS-CoV-2 , Vietnã/epidemiologiaRESUMO
BACKGROUND: Globally, most people with multidrug-resistant tuberculosis (MDR-TB) and their households experience catastrophic costs of illness, diagnosis, and care. However, the factors associated with experiencing catastrophic costs are poorly understood. This study aimed to identify risk factors associated with catastrophic costs incurrence among MDR-TB-affected households in Ho Chi Minh City (HCMC), Viet Nam. METHODS: Between October 2020 and April 2022, data were collected using a locally-adapted, longitudinal WHO TB Patient Cost Survey in ten districts of HCMC. Ninety-four people with MDR-TB being treated with a nine-month TB regimen were surveyed at three time points: after two weeks of treatment initiation, completion of the intensive phase and the end of the treatment (approximately five and 10 months post-treatment initiation respectively). The catastrophic costs threshold was defined as total TB-related costs exceeding 20% of annual pre-TB household income. Logistic regression was used to identify variables associated with experiencing catastrophic costs. A sensitivity analysis examined the prevalence of catastrophic costs using alternative thresholds and cost estimation approaches. RESULTS: Most participants (81/93 [87%]) experienced catastrophic costs despite the majority 86/93 (93%) receiving economic support through existing social protection schemes. Among participant households experiencing and not experiencing catastrophic costs, median household income was similar before MDR-TB treatment. However, by the end of MDR-TB treatment, median household income was lower (258 [IQR: 0-516] USD vs. 656 [IQR: 462-989] USD; p = 0.003), and median income loss was higher (2838 [IQR: 1548-5418] USD vs. 301 [IQR: 0-824] USD; p < 0.001) amongst the participant households who experienced catastrophic costs. Being the household's primary income earner before MDR-TB treatment (aOR = 11.2 [95% CI: 1.6-80.5]), having a lower educational level (aOR = 22.3 [95% CI: 1.5-344.1]) and becoming unemployed at the beginning of MDR-TB treatment (aOR = 35.6 [95% CI: 2.7-470.3]) were associated with experiencing catastrophic costs. CONCLUSION: Despite good social protection coverage, most people with MDR-TB in HCMC experienced catastrophic costs. Incurrence of catastrophic costs was independently associated with being the household's primary income earner or being unemployed. Revision and expansion of strategies to mitigate TB-related catastrophic costs, in particular avoiding unemployment and income loss, are urgently required.
Assuntos
Custos de Cuidados de Saúde , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Estudos Prospectivos , Vietnã/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , RendaRESUMO
BACKGROUND: There is extensive evidence for the cost-effectiveness of programmatic and additional tuberculosis (TB) interventions, but no studies have employed the social return on investment (SROI) methodology. We conducted a SROI analysis to measure the benefits of a community health worker (CHW) model for active TB case finding and patient-centered care. METHODS: This mixed-method study took place alongside a TB intervention implemented in Ho Chi Minh City, Viet Nam, between October-2017 - September-2019. The valuation encompassed beneficiary, health system and societal perspectives over a 5-year time-horizon. We conducted a rapid literature review, two focus group discussions and 14 in-depth interviews to identify and validate pertinent stakeholders and material value drivers. We compiled quantitative data from the TB program's and the intervention's surveillance systems, ecological databases, scientific publications, project accounts and 11 beneficiary surveys. We mapped, quantified and monetized value drivers to derive a crude financial benefit, which was adjusted for four counterfactuals. We calculated a SROI based on the net present value (NPV) of benefits and investments using a discounted cash flow model with a discount rate of 3.5%. A scenario analysis assessed SROI at varying discount rates of 0-10%. RESULTS: The mathematical model yielded NPVs of US$235,511 in investments and US$8,497,183 in benefits. This suggested a return of US$36.08 for each dollar invested, ranging from US$31.66-US39.00 for varying discount rate scenarios. CONCLUSIONS: The evaluated CHW-based TB intervention generated substantial individual and societal benefits. The SROI methodology may be an alternative for the economic evaluation of healthcare interventions.