Oncologist-Reported Barriers and Facilitators to Offering Cancer Clinical Trials to Their Patients.

NCCN guidelines indicate that cancer clinical trials (CCTs) are the best management for patients with cancer. However, only 5% of patients enroll in them. We examined oncologists' perceived barriers and facilitators to discussing CCTs. This qualitative study was part of the ASCO-ACCC Initiative to Increase Racial and Ethnic Diversity in Clinical Trials. Barriers and facilitators at the system, trial, provider, and patient levels were examined. To achieve triangulation, patient encounters were reviewed using chart-stimulated recall (CSR) methods, thereby obtaining a valid assessment of physician performance. Ten oncology providers participated in this study. Nine were oncologists, and one was a clinical research coordinator; five were female; four were White; three were Asian; and three were Black. Barriers to offering CCTs were a lack of trial availability; ineligibility; a lack of knowledge; assumptions about patient interest, benefits, or harms; patient's disease factors; and negative attitudes. Facilitators of offering CCTs were a physical space to discuss trials; greater trial availability; a systematic approach to offering trials; patient factors; patients seeking trials; a lack of comorbidities; patients being younger in age; patients being aware of, asking about, or hearing of trials from their surgeon; and higher levels of altruism. Many of the cited barriers are addressable with the cited facilitators. A larger study is needed to generalize and validate these findings.

A short treatment with resveratrol after a renal ischaemia-reperfusion injury prevents maladaptive repair and long-term chronic kidney disease in rats.

Acute kidney injury (AKI) often triggers physiological processes aimed at restoring renal function and architecture. However, this response can become maladaptive, leading to nephron loss and fibrosis. Although the therapeutic effects of resveratrol (RSV) are well established, its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. This study assessed whether transient administration of RSV following ischaemia-reperfusion injury (IRI) could prevent the progression to CKD. Forty-one male Wistar rats were assigned randomly to sham surgery, bilateral renal ischaemia for 30 min (IR) or IR+RSV. The RSV treatment commenced 24 h after IRI and continued for 10 days. The rats were studied for either 10 days or 5 months, after which kidney function and structure were evaluated. Mitochondrial homeostasis, oxidant defence and renal inflammation state were also evaluated. Despite having the same severity of AKI, rats receiving RSV for 10 days after IRI exhibited significant improvement in kidney histological injury and reduced inflammation, although renal haemodynamic recovery was less pronounced. Resveratrol effectively prevented the elevation of tubular injury-related molecules and profibrotic signalling with reduced myofibroblast proliferation. Furthermore, RSV substantially improved the antioxidant response and mitochondrial homeostasis. After 5 months, RSV prevented the transition to CKD, as evidenced by the prevention of progressive proteinuria, renal dysfunction and tubulointerstitial fibrosis. This study demonstrates that a brief treatment with RSV following IRI is enough to prevent maladaptive repair and the development of CKD. Our findings highlight the importance of the early days of reperfusion, indicating that maladaptive responses can be reduced effectively following severe AKI. KEY POINTS: Physiological processes activated after acute kidney injury (AKI) can lead to maladaptive responses, causing nephron loss and fibrosis. Prophylactic renoprotection with resveratrol (RSV) has been described in experimental AKI, but its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. In this study, we found that histological tubular injury persists 10 days after ischaemia-reperfusion injury and contributes to a failed repair phenotype in proximal tubular cells. Short-term RSV intervention influenced the post-ischaemic repair response and accelerated tubular recovery by reducing oxidative stress and mitochondrial damage. Furthermore, RSV targeted inflammation and profibrotic signalling during the maladaptive response, normalizing both processes. Resveratrol effectively prevented AKI-to-CKD transition even 5 months after the intervention. The study serves as a proof of concept, proposing RSV as a valuable candidate for further translational clinical studies to mitigate AKI-to-CKD transition.

Interventions to Mitigate Financial Toxicity in Adult Patients with Cancer in the United States: A Scoping Review.

Financial toxicity adversely affects quality of life and treatment outcomes for patients with cancer. This scoping review examined interventions aimed at mitigating financial toxicity in adult patients with cancer and their effectiveness. We utilized five bibliographical databases to identify studies that met our inclusion criteria. The review included studies conducted among adult patients with cancer in the United States and published in English between January 2011 to March 2023. The review identified eight studies that met the inclusion criteria. Each of the studies discussed the implementation of interventions at the patient/provider and/or health system level. Collectively, the findings from this scoping review highlight both the limited number of published studies that are aimed at mitigating financial toxicity and the need to create and assess interventions that directly impact financial toxicity in demographically diverse populations of adult patients with cancer.

Multi-Cancer Early Detection: The New Frontier in Cancer Early Detection.

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.

Time to Cancer Treatment and Chemotherapy Relative Dose Intensity for Patients With Breast Cancer Living With HIV.

Importance: Patients with breast cancer and comorbid HIV experience higher mortality than other patients with breast cancer. Objective: To compare time to cancer treatment initiation and relative dose intensity (RDI) of neoadjuvant and adjuvant chemotherapy among patients with breast cancer with vs without HIV. Design, Setting, and Participants: A retrospective, matched cohort study enrolled women who received a diagnosis of breast cancer from January 1, 2000, through December 31, 2018. The electronic medical records of 3 urban, academic cancer centers were searched for women with confirmed HIV infection prior to or simultaneous with diagnosis of stage I to III breast cancer. Tumor registry data were used to identify 2 control patients with breast cancer without HIV for each participant with HIV, matching for study site, stage, and year of cancer diagnosis. Statistical analysis was performed from December 2022 to October 2023. Exposure: HIV infection detected before or within 90 days of participants' breast cancer diagnosis. Main Outcomes and Measures: The primary outcome was time to breast cancer treatment initiation, defined as the number of days between cancer diagnosis and first treatment. The secondary outcome was overall RDI for patients who received chemotherapy. These outcomes were compared by HIV status using Cox proportional hazards regression and linear regression modeling, respectively, adjusting for confounding demographic and clinical factors. Exploratory outcomes included instances of anemia, neutropenia, thrombocytopenia, and liver function test result abnormalities during chemotherapy, which were compared using Fisher exact tests. Results: The study enrolled 66 women with comorbid breast cancer and HIV (median age, 51.1 years [IQR, 45.7-58.2 years]) and 132 with breast cancer alone (median age, 53.9 years [IQR, 47.0-62.5 years]). The median time to first cancer treatment was not significantly higher among patients with HIV than those without (48.5 days [IQR, 32.0-67.0 days] vs 42.5 days [IQR, 25.0-59.0 days]; adjusted hazard ratio, 0.78, 95% CI, 0.55-1.12). Among the 36 women with HIV and 62 women without HIV who received chemotherapy, the median overall RDI was lower for those with HIV vs without HIV (0.87 [IQR, 0.74-0.97] vs 0.96 [IQR, 0.88-1.00]; adjusted P = .01). Grade 3 or higher neutropenia during chemotherapy occurred among more women with HIV than those without HIV (13 of 36 [36.1%] vs 5 of 58 [8.6%]). Conclusions and Relevance: This matched cohort study suggests that patients with breast cancer and HIV may have experienced reduced adjuvant chemotherapy RDI, reflecting greater dose reductions, delays, or discontinuation. Strategies for supporting this vulnerable population during chemotherapy treatment are necessary.

The role of TNF receptors as mediators of chronic vasculitis in possible milder forms of the CNS tuberculosis.

INTRODUCTION: Central nervous system (CNS) tuberculosis (TB) is the most severe form of TB due to its high mortality and functional sequelae. There are several differential diagnoses for TB; and, it can also cause secondary conditions, such as vasculitis. METHODOLOGY: 155 biopsies, corresponding to 155 different patients out of 5,386 registered biopsies from 2008-2013, met the criteria of unknown etiology vasculitis and evidence of cerebral vascular disease. These were analyzed to assess the presence of central nervous system TB. The selected cases were assessed with Suzaan Marais (SM) criteria for clinical tuberculosis. After that, Ziehl-Neelsen (ZN) staining and polymerase chain reaction (PCR) were performed to amplify a fragment of the insertion sequence IS6110 of M. tuberculosis. 21 patients met the criteria for definitive tuberculosis by ZN staining and PCR, and 2 met the criteria for possible tuberculosis. Tumor necrosis factor (TNF)-α, TNF-R1, and TNF-R2 were determined by immunohistochemistry in histological sections from formalin-fixed paraffin-embedded (FF-PE) tissues in the 23 selected patients. RESULTS: Granulomatous TB was present in almost half of the cases. TNF-R1 and TNF-R2 were expressed mainly in blood vessels, histiocytes, and macrophages. TNF-R2 expression was higher than the other markers, which suggests an anti-inflammatory response against M. tuberculosis. CONCLUSIONS: The histopathological presentation of TB is not always limited to granulomas, abscesses, or meningitis; there are also clinical presentations characterized only with chronic inflammation of nervous and vascular tissue.

Validación de la escala Techo de Cristal en trabajadoras durante la pandemia / Validation of the glass ceiling scale in female workers during the pandemic

Resumen En el ámbito laboral, algunas condiciones basadas en estereotipos sociales promueven la obstaculización para que una mujer trabajadora acceda a las mismas oportunidades de desarrollo profesional; por ello, el objetivo de este estudio fue crear y validar la Escala Techo de Cristal. Se realizó un estudio empírico instrumental con una muestra no probabilística de 203 mujeres mexicanas, que trabajaban durante la pandemia por COVID-19. El Análisis Factorial Exploratorio y Análisis Factorial Confirmatorio arrojaron valores de índice de ajuste aceptables (NFI = .832, TLI = .900, CFI = .918, y RMSEA = .62) y con un coeficiente de confiabilidad de α = .816. La escala quedó conformada por 15 reactivos en tres factores: Sobrecarga, Techo de Cristal y Balance Familia-Trabajo, siendo el modelo de tres factores la estructura idónea para medir el constructo. Los resultados brindan evidencia de que el instrumento cuenta con las propiedades psicométricas para ser utilizado en la población de estudio y con ello generar diagnósticos confiables que deriven en estrategias organizacionales para visibilizar y de ser posible erradicar este fenómeno.

Abstract In the workplace, some conditions based on social stereotypes hinder a working woman from accessing the same professional development opportunities as a male; therefore, the purpose of this research paper was to create and validate the Glass Ceiling Scale. An instrumental empirical study was carried out with a non-probabilistic sample of 203 Mexican women who worked during the Covid-19 pandemic. The Exploratory Factor Analysis and Confirmatory Factor Analysis yielded acceptable fit index values (NFI = .832, TLI = .900, CFI = .918, and RMSEA= .62) and with a reliability coefficient of α = .816. The scale was made up of 15 items in three factors: Overload, Glass Ceiling and Family-Work Balance, with the three-factor model being the ideal structure to measure the construct. Results show evidence that the scale has the due psychometric properties for use in the study population and thereby generate reliable diagnoses that lead to organizational strategies to make visible and eradicate this phenomenon.

Central Nervous System Tuberculosis in a Murine Model: Neurotropic Strains or a New Pathway of Infection?

Tuberculosis (TB) of the central nervous system (CNS) is a lethal and incapacitating disease. Several studies have been performed to understand the mechanism of bacterial arrival to CNS, however, it remains unclear. Although the interaction of the host, the pathogen, and the environment trigger the course of the disease, in TB the characteristics of these factors seem to be more relevant in the genesis of the clinical features of each patient. We previously tested three mycobacterial clinical isolates with distinctive genotypes obtained from the cerebrospinal fluid of patients with meningeal TB and showed that these strains disseminated extensively to the brain after intratracheal inoculation and pulmonary infection in BALB/c mice. In this present study, BALB/c mice were infected through the intranasal route. One of these strains reaches the olfactory bulb at the early stage of the infection and infects the brain before the lungs, but the histological study of the nasal mucosa did not show any alteration. This observation suggests that some mycobacteria strains can arrive directly at the brain, apparently toward the olfactory nerve after infecting the nasal mucosa, and guides us to study in more detail during mycobacteria infection the nasal mucosa, the associated connective tissue, and nervous structures of the cribriform plate, which connect the nasal cavity with the olfactory bulb.

Mycobacterium tuberculosis Infection Induces BCSFB Disruption but No BBB Disruption In Vivo: Implications in the Pathophysiology of Tuberculous Meningitis.

Central nervous system (CNS) tuberculosis is the most lethal and devastating form among the diseases caused by Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis bacilli enter the CNS are still unclear. However, the BBB and the BCSFB have been proposed as possible routes of access into the brain. We previously reported that certain strains of M. tuberculosis possess an enhanced ability to cause secondary CNS infection in a mouse model of progressive pulmonary tuberculosis. Here, we evaluated the morphostructural and molecular integrity of CNS barriers. For this purpose, we analyzed through transmission electron microscopy the ultrastructure of brain parenchymal microvessels and choroid plexus epithelium from animals infected with two mycobacterial strains. Additionally, we determined the expression of junctional proteins and cytokines by immunological techniques. The results showed that the presence of M. tuberculosis induced disruption of the BCSFB but no disruption of the BBB, and that the severity of such damage was related to the strain used, suggesting that variations in the ability to cause CNS disease among distinct strains of bacteria may also be linked to their capacity to cause direct or indirect disruption of these barriers. Understanding the pathophysiological mechanisms involved in CNS tuberculosis may facilitate the establishment of new biomarkers and therapeutic targets.

Effect of Curcumin in Experimental Pulmonary Tuberculosis: Antimycobacterial Activity in the Lungs and Anti-Inflammatory Effect in the Brain.

Tuberculosis (TB) is one of the ten leading causes of death worldwide. Patients with TB have been observed to suffer from depression and anxiety linked to social variables. Previous experiments found that the substantial pulmonary inflammation associated with TB causes neuroinflammation, neuronal death, and behavioral impairments in the absence of brain infection. Curcumin (CUR) is a natural product with antioxidant, anti-inflammatory and antibacterial activities. In this work, we evaluated the CUR effect on the growth control of mycobacteria in the lungs and the anti-inflammatory effect in the brain using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive mycobacteria (strain H37Rv). The results have shown that CUR decreased lung bacilli load and pneumonia of infected animals. Finally, CUR significantly decreased neuroinflammation (expression of TNFα, IFNγ and IL12) and slightly increased the levels of nuclear factor erythroid 2-related to factor 2 (Nrf2) and the brain-derived neurotrophic factor (BDNF) levels, improving behavioral status. These results suggest that CUR has a bactericidal effect and can control pulmonary mycobacterial infection and reduce neuroinflammation. It seems that CUR has a promising potential as adjuvant therapy in TB treatment.

Clinical and pathological characteristics associated with the presence of the IS6110 Mycobacterim tuberculosis transposon in neoplastic cells from non-small cell lung cancer patients.

Lung cancer (LC) and pulmonary tuberculosis (TB) are the deadliest neoplastic and bacterial infectious diseases worldwide, respectively. Clinicians and pathologists have long discussed the co-existence of LC and TB, and several epidemiologic studies have presented evidence indicating that TB could be associated with the development of LC, particularly adenocarcinoma. Nonetheless, this data remains controversial, and the mechanism which could underlie the association remains largely unexplored. Some bioinformatic studies have shown that human cancer biopsies have a very high frequency of bacterial DNA integration; since Mycobacterium Tuberculosis (MTb) is an intracellular pathogen, it could play an active role in the cellular transformation. Our group performed an exploratory study in a cohort of 88 LC patients treated at the Instituto Nacional de Cancelorogía (INCan) of Mexico City to evaluate the presence of MTb DNA in LC tissue specimens. For the first time, our results show the presence of the MTb IS6110 transposon in 40.9% (n = 36/88) of patients with lung adenocarcinomas. Additionally, through in-situ PCR we identified the presence of IS6110 in the nuclei of tumor cells. Furthermore, shotgun sequencing from two samples identified traces of MTb genomes present in tumor tissue, suggesting that similar Mtb strains could be infecting both patients.

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity.

Metabolic syndrome is considered the precursor of type 2 diabetes mellitus. Tuberculosis is a leading infection that constitutes a global threat remaining a major cause of morbi-mortality in developing countries. People with type 2 diabetes mellitus are more likely to suffer from infection with Mycobacterium tuberculosis. For both type 2 diabetes mellitus and tuberculosis, there is pulmonary production of anti-inflammatory glucocorticoids mediated by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). The adrenal hormone dehydroepiandrosterone (DHEA) counteracts the glucocorticoid effects of cytokine production due to the inhibition of 11ß-HSD1. Late advanced tuberculosis has been associated with the suppression of the Th1 response, evidenced by a high ratio of cortisol/DHEA. In a murine model of metabolic syndrome, we determined whether DHEA treatment modifies the pro-inflammatory cytokines due to the inhibition of the 11ß-HSD1 expression. Since macrophages express 11ß-HSD1, our second goal was incubating them with DHEA and Mycobacterium tuberculosis to show that the microbicide effect was increased by DHEA. Enoyl-acyl carrier protein reductase (InhA) is an essential enzyme of Mycobacterium tuberculosis involved in the mycolic acid synthesis. Because 11ß-HSD1 and InhA are members of a short-chain dehydrogenase/reductase family of enzymes, we hypothesize that DHEA could be an antagonist of InhA. Our results demonstrate that DHEA has a direct microbicide effect against Mycobacterium tuberculosis; this effect was supported by in silico docking analysis and the molecular dynamic simulation studies between DHEA and InhA. Thus, DHEA increases the production of pro-inflammatory cytokines in the lung, inactivates GC by 11ß-HSD1, and inhibits mycobacterial InhA. The multiple functions of DHEA suggest that this hormone or its synthetic analogs could be an efficient co-adjuvant for tuberculosis treatment.

Clima escolar como factor protector para el consumo de drogas en adolescentes de preparatoria / School climate as a protective factor for substance use in high school adolescents

Resumen Marco contextual: El clima escolar se considera un factor protector para el consumo de drogas. Objetivo: Identificar la asociación del clima escolar con el consumo de drogas por los adolescentes. Metodología: Estudio descriptivo correlacional predictivo. Muestreo por conglomerados unietápico y una muestra de 227 estudiantes de 15 a 18 años. Se aplicó una Cédula de Identificación de Características Personales y Consumo de Drogas y la Escala de Clima Escolar (MDS3). Resultados: Se identificó que cuando existe percepción positiva de seguridad (OR = 0,904; p < 0,01), existe menor consumo de alcohol en la última semana, lo que explica el 8,2% de la varianza. Por otra parte, el clima escolar positivo no predice el consumo de tabaco, sin embargo, existe menor probabilidad de consumo de tabaco en el último año cuando existe una percepción positiva del ambiente escolar (OR = 0,884; p < 0,05). Conclusión: La percepción positiva de seguridad en el clima escolar se asocia con el no consumo de alcohol en la última semana, sin embargo, no predice el consumo de tabaco.

Abstract Background: The school climate is a protective factor for substance use. Objective: To identify the association between school climate and substance use in adolescents. Methodology: Predictive descriptive-correlational study. Single-stage cluster sampling and a sample of 227 students aged 15 to 18 years. A Personal Traits and Drug Consumption Identity Card and the School Climate Survey (MDS3) were applied. Results: Participants had a positive perception of safety (OR = 0.904; p < 0.01). There was less alcohol consumption in the last week, explaining 8.2% of the variance. Although a positive school climate does not predict tobacco use, a positive perception of the school environment results in a lower probability of tobacco use in the last year (OR = 0.884; p < 0.05). Conclusion: Although a positive perception of safety in the school climate is associated with no alcohol consumption in the last week, it does not predict tobacco use.

Resumo Enquadramento: O clima escolar é considerado um fator de proteção para o consumo de drogas. Objetivo: Identificar a associação do clima escolar com o uso de drogas por adolescentes. Metodologia: Estudo descritivo correlacional preditivo. Amostragem por conglomerados num estágio e amostra de 227 alunos de 15 a 18 anos. Foram aplicados o Cartão de Identificação de Características Pessoais e Consumo de Medicamentos e a Escala de Clima Escolar (MDS3). Resultados: Identificou-se que quando há perceção positiva de segurança (OR = 0,904; p < 0,01) há menor consumo de álcool na última semana, explicando 8,2% da variância. Por outro lado, um clima escolar positivo não prediz o uso de tabaco, porém, há menor probabilidade de uso de tabaco no último ano quando há uma perceção positiva do ambiente escolar (OR = 0,884; p < 0,05). Conclusão: A perceção positiva de segurança no clima escolar está associada ao não consumo de álcool na última semana, porém não prediz o uso de tabaco.

Targeted RNA-Seq Reveals the M. tuberculosis Transcriptome from an In Vivo Infection Model.

The study of host-pathogen interactions using in vivo models with intracellular pathogens like Mycobacterium tuberculosis (Mtb) entails technical limitations, such as: (i) Selecting an efficient differential lysis system to enrich the pathogen cells; (ii) obtaining sufficient high-quality RNA; and (iii) achieving an efficient rRNA depletion. Thus, some authors had used flow cytometers to separate infected cells or significantly increase the sequencing depth of host-pathogen RNA libraries to observe the pathogens' gene expression. However, these options carry additional expenses in specialized equipment typically not available for all laboratories. Here, we propose an experimental protocol involving differential cell lysis and a probe-based ribosomal depletion to determine the gene expression of Mtb and its host during in vivo infection. This method increased the number of observed pathogen-expressed genes from 13 using the traditional RNA-seq approach to 702. After eliminating rRNA reads, we observed that 61.59% of Mtb sequences represented 702 genes, while 38.41% represented intergenic regions. Some of the most expressed genes codified for IS1081 (Rv2512c) transposase and eight PE-PGRS members, such as PGRS49 and PGRS50. As expected, a critical percent of the expressed genes codified for secreted proteins essential for infection, such as PE68, lppN, and LpqH. Moreover, three Mtb ncRNAs were highly expressed (small RNA MTS2823, transfer-messenger RNA RF00023, and ribozyme RF00010). Many of the host-expressed genes were related to the inflammation process and the expression of surfactant proteins such as the Sftpa and Sftpc, known to bind Mtb to alveolar macrophages and mi638, a microRNA with no previous associations with pulmonary diseases. The main objective of this study is to present the method, and a general catalog of the Mtb expressed genes at one point of the in vivo infection. We believe our method represents a different approach to the existing ones to study host-pathogen interactions in tuberculosis and other similar intracellular infections, without the necessity of specialized equipment.

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis.

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone's (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.

16α-Bromoepiandrosterone as a new candidate for experimental diabetes-tuberculosis co-morbidity treatment.

Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-ß-hydroxysteroid dehydrogenase type 1 (11-ßHSD1). 11-ßHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-ß-hydroxysteroid dehydrogenase type 2 (11-ßHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-ßHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-ßHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-ßHSD1 expression while increasing 11-ßHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.

Immunotherapeutic effect of adenovirus encoding antimicrobial peptides in experimental pulmonary tuberculosis.

As components of the innate immune response, antimicrobial peptides (AMPs) efficiently contribute to infection control and maintenance of a latent state in pulmonary tuberculosis (TB). As a therapeutic strategy, the administration of recombinant AMPs could be limited by enzymatic degradation and high production costs. Likewise, strategies based on the induction of AMPs have generated controversial results. In this study, 2 recombinant type-5 adenoviruses (Ad) expressing the human ß-defensin 3 (HßD3) or cathelicidin (LL37) were assessed in a murine pulmonary TB model. Mice infected with either a high dose of a drug-sensitive (H37Rv) or a multidrug-resistant (MDR) strain of Mycobacterium tuberculosis (Mtb) were treated with a single administration of AdHßD3, AdLL37, AdGFP (control vector expressing a green fluorescent protein), or saline solution (SS). Lungs were obtained to determine the bacterial burden, histologic damage, and cytokine expression at different time points. Mice treated with AdHßD3 or AdLL37 showed significantly lower bacterial load and pneumonia, and higher proinflammatory cytokine expression than the control groups AdGFP and SS. A synergistic therapeutic effect could be observed when first- or second-line antibiotics (ABs) were administered with adenoviral therapy in animals infected with H37Rv or MDR strains, respectively. Adenovirus-delivered AMP's administration constitutes a promising adjuvant therapy for current anti-TB drugs by enhancing a protective immune response and potentially reducing current AB regimes' duration.

Backtesting VaR under the COVID-19 sudden changes in volatility.

We analyze the impact of the COVID-19 pandemic on the conditional variance of stock returns. We look at this effect from a global perspective, so we employ series of major stock market and sector indices. We use the Hansen's Skewed-t distribution with EGARCH extended to control for sudden changes in volatility. We oversee the COVID-19 effect on measures of downside risk such as the Value-at-Risk. Our results show that there is a significant sudden shift up in the return distribution variance post the announcement of the pandemic, which must be explained properly to obtain reliable measures for financial risk management.

Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice.

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.

Erratum: Author Correction: BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines.

[This corrects the article DOI: 10.1038/s41541-020-0169-6.].