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BACKGROUND: Tuberculosis (TB) infectiousness decreases significantly with only a few days of treatment, but delayed diagnosis often leads to late treatment initiation. We conducted a sequential explanatory mixed methods study to understand the barriers and facilitators to prompt diagnosis among people with TB. METHODS: We enrolled 100 adults who started TB treatment in the Carabayllo district of Lima, Peru, between November 2020 and February 2022 and administered a survey about their symptoms and healthcare encounters. We calculated total diagnostic delay as time from symptom onset to diagnosis. We conducted semi-structured interviews of 26 participants who had a range of delays investigating their experience navigating the health system. Interview transcripts were inductively coded for concepts related to diagnostic barriers and facilitators. RESULTS: Overall, 38% of participants sought care first from public facilities and 42% from the private sector. Only 14% reported being diagnosed with TB on their first visit, and participants visited a median of 3 (interquartile range [IQR] health facilities before diagnosis. The median total diagnostic delay was 9 weeks (interquartile range [IQR] 4-22), with a median of 4 weeks (IQR 0-9) before contact with the health system and of 3 weeks (IQR 0-9) after. Barriers to prompt diagnosis included participants attributing their symptoms to an alternative cause or having misconceptions about TB, and leading them to postpone seeking care. Once connected to care, variations in clinical management, health facility resource limitations, and lack of formal referral processes contributed to the need for multiple healthcare visits before obtaining a diagnosis. Facilitators to prompt diagnosis included knowing someone with TB, supportive friends and family, referral documents, and seeing a pulmonologist. CONCLUSIONS: Misinformation about TB among people with TB and providers, poor accessibility of health services, and the need for multiple encounters to obtain diagnostic tests were major factors leading to delays. Extending the hours of operation of public health facilities, improving community awareness and provider training, and creating a formal referral process between the public and private sectors should be priorities in the efforts to combat TB.
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Diagnóstico Tardío , Tuberculosis , Humanos , Perú , Adulto , Masculino , Femenino , Diagnóstico Tardío/estadística & datos numéricos , Tuberculosis/diagnóstico , Persona de Mediana Edad , Accesibilidad a los Servicios de Salud , Adulto Joven , Aceptación de la Atención de Salud/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
In Latin America, little is known about the involvement of private health-care providers in tuberculosis (TB) detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in North Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private health-care providers and 5 key informants. We estimated that 77% of patients sought care initially at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public-sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Private providers believed they offered shorter wait times and a faster diagnosis, but they struggled with a lack of referral systems and communication with the public sector. Nonrecognition of private-sector tests by the public sector led to duplicate testing of referred patients. Although expressing willingness to collaborate with public-sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.
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Sector Privado , Tuberculosis , Humanos , Perú/epidemiología , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Tuberculosis/terapia , Sector Público , Personal de Salud , Aceptación de la Atención de SaludRESUMEN
The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.
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Composición Familiar , Tamizaje Masivo , Radiografía Torácica , Humanos , Perú/epidemiología , Masculino , Femenino , Adulto , Adolescente , Adulto Joven , Tamizaje Masivo/métodos , Estudios Longitudinales , Persona de Mediana Edad , Niño , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/diagnóstico por imagen , Trazado de Contacto/métodos , Preescolar , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Tuberculosis Latente/diagnóstico por imagen , Lactante , Tuberculosis/epidemiología , Tuberculosis/diagnóstico , Tuberculosis/diagnóstico por imagenRESUMEN
Rationale: The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority. Objectives: We aimed to identify characteristics of individuals involved in TB transmission in a community setting, which may guide the prioritization of targeted interventions. Methods: We collected clinical and sociodemographic data from a cohort of patients with TB in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs, and we assumed that the first diagnosed patient in a pair was the transmitter and the second was the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct TB transmission. Measurements and Main Results: Analyzing data from 2,518 index patients with TB, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. Conclusions: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend TB screening to social groups such as young adults and prisoners with limited access to routine preventive care.
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Tuberculosis , Humanos , Perú/epidemiología , Masculino , Femenino , Adulto , Estudios Transversales , Persona de Mediana Edad , Adulto Joven , Estudios de Cohortes , Tuberculosis/transmisión , Tuberculosis/epidemiología , Adolescente , Factores de Riesgo , Secuenciación Completa del Genoma , AncianoRESUMEN
Traumatic brain injury has been the leading cause of mortality and morbidity in human beings. One of the most susceptible structures to this damage is the hippocampus due to cellular and synaptic loss and impaired hippocampal connectivity to the brain, brain stem, and spinal cord. Thus, hippocampal damage in rodents using a stereotaxic device could be an adequate method to study a precise lesion from CA1 to the dentate gyrus structures. We studied male and female rats and mice, analyzing hindlimb locomotion kinematics changes to compare the locomotion kinematics using the same methodology in rodents. We measure (1) the vertical hindlimb metatarsus, ankle, and knee joint vertical displacements (VD) and (2) the factor of dissimilarity (DF). The VD in intact rats in metatarsus, ankle, and knee joints differs from that in intact mice in similar joints. In rats, the vertical displacement through the step cycle changed in the left and right metatarsus, ankle, and knee joints compared to the intact group versus the lesioned group. More subtle changes were also observed in mice. DF demonstrates contrasting results when studying locomotion kinematics of mice or rats and sex-dependent differences. Thus, a precise lesion in a rodent's hippocampal structure discloses some hindlimb locomotion changes related to species and sex. Thus, we only have a qualitative comparison between murine species. In order to make a comparison with other species, we should standardize the model.
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We explored the utility of brief Mycobacterium tuberculosis whole-genome sequencing (WGS) "snapshots" at a sentinel site within Lima, Peru for evaluating local transmission dynamics over time. Within a 17 km2 area, 15/70 (21%) isolates with WGS collected during 2011-2012 and 22/81 (27%) collected during 2020-2021 were clustered (p = 0.414), and additional isolates clustered with those from outside the area. Isolates from the later period were disproportionately related to large historic clusters in Lima from the earlier period. WGS snapshots at a sentinel site may not be useful for monitoring transmission, but monitoring the persistence of large transmission clusters might be.
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OBJECTIVE: To develop a framework to estimate the practical costs incurred from, and programmatic impact related to, tuberculosis (TB) infection testing-tuberculin skin tests (TST) versus interferon gamma release assay (IGRA)-in a densely populated high-burden TB area. METHODS: We developed a seven-step framework that can be tailored to individual TB programmes seeking to compare TB infection (TBI) diagnostics to inform decision-making. We present methodology to estimate (1) the prevalence of TBI, (2) true and false positives and negatives for each test, (3) the cost of test administration, (4) the cost of false negatives, (5) the cost of treating all that test positive, (6) the per-test cost incurred due to treatment and misdiagnosis and (7) the threshold at which laboratory infrastructure investments for IGRA are outweighed by system-wide savings incurred due to IGRA utilisation. We then applied this framework in a densely populated, peri-urban district in Lima, Peru with high rates of Bacillus Calmette-Guérin (BCG) vaccination. FINDINGS: The lower sensitivity of TST compared with IGRA is a major cost driver, leading to health system and societal costs due to misdiagnosis. Additionally, patient and staff productivity costs were greater for TST because it requires two patient visits compared with only one for IGRA testing. When the framework was applied to the Lima setting, we estimate that IGRA-associated benefits outweigh infrastructural costs after performing 672 tests. CONCLUSIONS: Given global shortages of TST and concerns about costs of IGRA testing and laboratory capacity building, this costing framework can provide public health officials and TB programmes guidance for decision-making about TBI testing locally. This framework was designed to be adaptable for use in different settings with available data. Diagnostics that increase accuracy or mitigate time to treatment should be thought of as an investment instead of an expenditure.
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Tuberculosis Latente , Tuberculosis , Humanos , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Ensayos de Liberación de Interferón gamma/métodos , Prueba de Tuberculina/métodos , Gastos en SaludRESUMEN
In Latin America, little is known about the involvement of private healthcare providers in TB detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private healthcare providers and 5 key informants. We estimated that 77% of patients initially sought care at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. The lack of TB services at initial care-seeking location was driven by the 41% of patients estimated to seek care first at a private facility. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Interviews revealed that private providers believed that they offered shorter wait times and a quicker diagnosis, but they struggled with a lack of follow-up systems and communication barriers with the public sector. While expressing willingness to collaborate with public sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.
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OBJECTIVE.: To evaluate the association between overweight/obesity and multidrug resistance in patients with and without a history of tuberculosis treatment. MATERIALS AND METHODS.: Cross-sectional study of secondary data from a tuberculosis cohort, which included anthropometric and drug-sensitivity testing data at the baseline visit of patients with and without previous tuberculosis treatment. RESULTS.: We evaluated 3,734 new cases and 766 with a history of having received treatment for tuberculosis. Overweight/obesity was not associated with multidrug resistance in patients with a history of tuberculosis treatment, with a prevalence ratio of 0.97 and a 95% confidence interval of 0.68-1.38. CONCLUSIONS.: Overweight/obesity is not associated with multidrug resistance in tuberculosis. Overweight/obesity is a dynamic process that may influence the relationship between the immune system and the metabolic system.
OBJETIVO.: Evaluar la asociación entre el sobrepeso/obesidad y la multidrogoresistencia en pacientes con y sin antecedentes de tratamiento para tuberculosis. MATERIALES Y MÉTODOS.: Estudio transversal realizado a través de un análisis secundario de la base de datos de una cohorte de tuberculosis, que incluyó datos de pruebas antropométricas y pruebas de sensibilidad a drogas en la visita basal de pacientes con y sin tratamiento previo para tuberculosis. RESULTADOS.: Se evaluaron 3,734 casos nuevos y 766 con antecedente de haber recibido tratamiento para tuberculosis. El sobrepeso/obesidad no se asoció a la multidrogoresistencia en pacientes con antecedente de tratamiento para tuberculosis, mostrando una razón de prevalencia de 0,97 con un intervalo de confianza al 95% de 0,68-1,38. CONCLUSIONES.: El sobrepeso/obesidad no está asociado a la multidrogoresistencia en tuberculosis; siendo el sobrepeso/obesidad un proceso dinámico que puede influir en las relaciones entre el sistema inmune y el sistema metabólico.
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Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/uso terapéutico , Sobrepeso/epidemiología , Estudios Transversales , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities.
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Everolimus , Neoplasias Renales , Femenino , Humanos , Anciano , Everolimus/efectos adversos , Monitoreo de Drogas , Citocromo P-450 CYP3A , Interacciones FarmacológicasRESUMEN
Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility, producing a loss of functional motor independence. We used a GBM xenograft implanted in the striatum to analyze the changes in Y (vertical) and X (horizontal) axis displacement of the metatarsus, ankle, and knee. We analyzed the steps dissimilarity factor between control and GBM mice with and without anastrozole. The body weight of the untreated animals decreased compared to treated mice. Anastrozole reduced the malignant cells and decreased GPR30 and ERα receptor expression. In addition, we observed a partial recovery in metatarsus and knee joint displacement (dissimilarity factor). The vertical axis displacement of the GBM+anastrozole group showed a difference in the right metatarsus, right knee, and left ankle compared to the GBM group. In the horizontal axis displacement of the right metatarsus, ankle, and knee, the GBM+anastrozole group exhibited a difference at the last third of the step cycle compared to the GBM group. Thus, anastrozole partially modified joint displacement. The dissimilarity factor and the vertical and horizontal displacements study will be of interest in GBM patients with locomotion alterations. Hindlimb displacement and gait locomotion analysis could be a valuable methodological tool in experimental and clinical studies to help diagnose locomotive deficits related to GBM.
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Objetivo. Evaluar la asociación entre el sobrepeso/obesidad y la multidrogoresistencia en pacientes con y sin antecedentes de tratamiento para tuberculosis. Materiales y métodos. Estudio transversal realizado a través de un análisis secundario de la base de datos de una cohorte de tuberculosis, que incluyó datos de pruebas antropométricas y pruebas de sensibilidad a drogas en la visita basal de pacientes con y sin tratamiento previo para tuberculosis. Resultados. Se evaluaron 3,734 casos nuevos y 766 con antecedente de haber recibido tratamiento para tuberculosis. El sobrepeso/obesidad no se asoció a la multidrogoresistencia en pacientes con antecedente de tratamiento para tuberculosis, mostrando una razón de prevalencia de 0,97 con un intervalo de confianza al 95% de 0,68-1,38. Conclusiones. El sobrepeso/obesidad no está asociado a la multidrogoresistencia en tuberculosis; siendo el sobrepeso/obesidad un proceso dinámico que puede influir en las relaciones entre el sistema inmune y el sistema metabólico.
Objective. To evaluate the association between overweight/obesity and multidrug resistance in patients with and without a history of tuberculosis treatment. Materials and methods. Cross-sectional study of secondary data from a tuberculosis cohort, which included anthropometric and drug-sensitivity testing data at the baseline visit of patients with and without previous tuberculosis treatment. Results. We evaluated 3,734 new cases and 766 with a history of having received treatment for tuberculosis. Overweight/obesity was not associated with multidrug resistance in patients with a history of tuberculosis treatment, with a prevalence ratio of 0.97 and a 95% confidence interval of 0.68-1.38. Conclusions. Overweight/obesity is not associated with multidrug resistance in tuberculosis. Overweight/obesity is a dynamic process that may influence the relationship between the immune system and the metabolic system.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Using data from 388 people diagnosed with tuberculosis through a community-based screening program in Lima, Peru, we estimated that cough screening followed by sputum smear microscopy would have detected only 23% of cases found using an algorithm of radiographic screening followed by rapid nucleic acid amplification testing and clinical evaluation.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Tuberculosis/diagnóstico , Tamizaje Masivo , Técnicas de Amplificación de Ácido Nucleico , Algoritmos , Perú/epidemiología , Esputo , Mycobacterium tuberculosis/genética , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The COVID-19 pandemic disrupted TB services worldwide, leading to diagnostic delays. There have been few published reports describing how the pandemic affected people's pathway to diagnosis from their own perspectives. We sought to evaluate the impact on the pandemic on people's experiences obtaining a TB diagnosis. METHODS: We performed a mixed-methods study, enrolling newly diagnosed TB patients from 12 health centers in Lima, Peru. We used structured surveys to quantify diagnostic delay, defined as the time between symptom onset and diagnosis, and in-depth interviews to understand the ways in which the pandemic affected the pathway to care. We compared diagnostic delay between patients enrolled during the first year of the pandemic to those diagnosed after using a Wilcoxon rank-sum test. We used an inductive content analysis approach to analyze interview content related to the pandemic. RESULTS: We enrolled 51 patients during November 2020-April 2021 (during the first year of the pandemic) and 49 patients during October 2021-February 2022. Median diagnostic delay was longer for patients diagnosed during the first year of the pandemic (median 15 [IQR 5-26] weeks compared to 6 [IQR 3-18] weeks, p = 0.027). Qualitative analysis of 26 interviews revealed that the pandemic affected participants' care-seeking behavior and their ability to access to TB diagnostic services, particularly for those diagnosed in the first year of the pandemic. Many participants initially had their symptoms attributed to COVID-19, resulting in delayed TB evaluation and additional costs for COVID-19 treatment. CONCLUSIONS: The COVID-19 pandemic impacted multiple steps in the pathway to care for TB patients in Lima, causing delays in TB diagnosis. These findings demonstrate how the shifting of health care resources to prioritize COVID-19 can lead to collateral damage for people with TB and other conditions.
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COVID-19 , Tuberculosis , Humanos , COVID-19/diagnóstico , Diagnóstico Tardío , Pandemias , Perú/epidemiología , Estudios Transversales , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis/terapia , Tratamiento Farmacológico de COVID-19RESUMEN
Spatially targeted interventions may be effective alternatives to individual or population-based prevention strategies against tuberculosis (TB). However, their efficacy may depend on the mechanisms that lead to geographically constrained hotspots. Local TB incidence may reflect high levels of local transmission; conversely, they may point to frequent travel of community members to high-risk areas. We used whole-genome sequencing to explore patterns of TB incidence and transmission in Lima, Peru. Between 2009 and 2012, we recruited incident pulmonary TB patients and their household contacts, whom we followed for the occurrence of TB disease. We used whole-genome sequences of 2,712 Mycobacterial tuberculosis isolates from 2,440 patients to estimate pariwise genomic distances and compared these to the spatial distance between patients' residences. Genomic distances increased rapidly as spatial distances increased and remained high beyond 2 km of separation. Next, we divided the study catchment area into 1 × 1 km grid-cell surface units and used household spatial coordinates to locate each TB patient to a specific cell. We estimated cell-specific transmission by calculating the proportion of patients in each cell with a pairwise genomic distance of 10 or fewer single-nucleotide polymorphisms. We found that cell-specific TB incidence and local transmission varied widely but that cell-specific TB incidence did not correlate closely with our estimates of local transmission (Cohen's k = 0.27). These findings indicate that an understanding of the spatial heterogeneity in the relative proportion of TB due to local transmission may help guide the implementation of spatially targeted interventions.
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Mycobacterium tuberculosis , Tuberculosis Pulmonar , Tuberculosis , Humanos , Perú/epidemiología , Tuberculosis/epidemiología , Mycobacterium tuberculosis/genética , Tuberculosis Pulmonar/epidemiología , Secuenciación Completa del GenomaRESUMEN
Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.
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Tuberculosis , Estudios de Casos y Controles , Humanos , Tamizaje Masivo , Prisiones , Transportes , Tuberculosis/diagnóstico , Tuberculosis/epidemiologíaRESUMEN
We investigated whether ancestry-specific genetic factors affect tuberculosis (TB) progression risk in a cohort of admixed Peruvians. We genotyped 2,105 patients with TB and 1,320 household contacts (HHCs) who were infected with Mycobacterium tuberculosis (M. tb) but did not develop TB and inferred each individual's proportion of native Peruvian genetic ancestry. Our HHC study design and our data on potential confounders allowed us to demonstrate increased risk independent of socioeconomic factors. A 10% increase in individual-level native Peruvian genetic ancestry proportion corresponded to a 25% increased TB progression risk. This corresponds to a 3-fold increased risk for individuals in the highest decile of native Peruvian genetic ancestry versus the lowest decile, making native Peruvian genetic ancestry comparable in effect to clinical factors such as diabetes. Our results suggest that genetic ancestry is a major contributor to TB progression risk and highlight the value of including diverse populations in host genetic studies.
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Spontaneous interneuron activity plays a critical role in developing neuronal networks. Discharges conducted antidromically along the dorsal root (DR) precede those from the ventral root's (VR) motoneurons. This work studied whether spinal interneurons project axons into the neonate's dorsal roots. Experiments were carried out in postnatal Swiss-Webster mice. We utilized a staining technique and found that interneurons in the spinal cord's dorsal horn send axons through the dorsal roots. In vitro electrophysiological recordings showed antidromic action potentials (dorsal root reflex; DRR) produced by depolarizing the primary afferent terminals. These reflexes appeared by stimulating the adjacent dorsal roots. We found that bicuculline reduced the DRR evoked by L5 dorsal root stimulation when recording from the L4 dorsal root. Simultaneously, the monosynaptic reflex (MR) in the L5 ventral root was not affected; nevertheless, a long-lasting after-discharge appeared. The addition of 2-amino-5 phosphonovaleric acid (AP5), an NMDA receptor antagonist, abolished the MR without changing the after-discharge. The absence of DRR and MR facilitated single action potentials in the dorsal and ventral roots that persisted even in low Ca2+ concentrations. The results suggest that firing interneurons could send their axons through the dorsal roots. These interneurons could activate motoneurons producing individual spikes recorded in the ventral roots. Identifying these interneurons and the persistence of their neuronal connectivity in adulthood remains to be established.
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Glioblastoma is the most frequent primary tumor in the human brain. Glioblastoma cells express aromatase and the classic estrogen receptors ERα and ERß and can produce estrogens that promote tumor growth. The membrane G protein-coupled estrogen receptor (GPER) also plays a significant role in numerous types of cancer; its participation in glioblastoma tumor development is not entirely known. The present study investigated the effect of the agonists [17ß-estradiol (E2) and G1] and antagonist (G15) of GPER on proliferation and apoptosis of C6 glioblastoma cells. GPER expression was evaluated by immunofluorescence, western blotting and reverse transcription-quantitative PCR. Cell proliferation was determined using Ki67 immunopositivity. Cell viability was examined using the MTT assay and apoptosis using caspase-3 immunostaining and ELISA. C6 cells express GPER, and the immunopositivity increased after exposure to E2, G1, or their combination. GPER protein expression increased after treatment with E2 combined with G1. However, GPER mRNA expression decreased in treated cells compared with control. The percentage of Ki67 immunopositive C6 cells increased under the effect of E2 in combination with G1 or G1 alone. G15 significantly reduced Ki67 immunopositivity. Pearson's correlation analysis revealed a positive relationship between GPER and Ki67 immunopositivity across the study conditions. Additionally, the MTT assay showed a significant reduction in C6 cell viability after G15 treatment, alone or in combination with G1. The exposure to G15 increased the percentage of caspase-3 immunopositivity cells and caspase-3 levels. Pearson's correlation analysis demonstrated a negative correlation between GPER and caspase-3 immunopositivity across the study conditions. Glioblastoma C6 cells express GPER, and this receptor modulates cell proliferation and apoptosis. The GPER agonists E2 and G1 favored cell proliferation; meanwhile, the antagonist G15 reduced cell proliferation, viability and favored apoptosis. Therefore, GPER may be used as a biomarker of glioblastoma and as a target to develop new therapeutic strategies for glioblastoma treatment.