Masa nasal como único compromiso extrapulmonar de infección por M. Tuberculosis / Nasal mass as the only extrapulmonary compromise of M. Tuberculosis infection / Massa nasal como único compromisso extrapulmonar da infecção por M. Tuberculose

La tuberculosis aún es un problema de salud pública mundial. La infección causada por Mycobacterium tuberculosis se manifiesta de forma principal a nivel pulmonar. Sin embargo, alrededor del 20 % de los casos se presentan en otras localizaciones anatómicas y solo el 2 % tiene afectación del tracto respiratorio superior. Se presenta el caso de una mujer de 75 años, reconsultante al servicio de otorrinolaringología por epistaxis, lesiones postillosas en cavidad nasal y hallazgo de masa nasal. Posterior a la resección quirúrgica de la lesión, se logró la comprobación microbiológica de infección por M. tuberculosis. Se realizan estudios para descartar compromiso pulmonar y de otras localizaciones. Posterior al inicio de tratamiento antituberculoso se logró resolución completa de la lesión y no recurrencia de los síntomas. Las formas extrapulmonares de la infección por M. tuberculosis y, en especial las que afectan la región de la cabeza y el cuello, requieren un alto índice de sospecha para su diagnóstico. Los métodos de diagnóstico como la prueba de PCR y los cultivos de tejidos permiten un óptimo inicio del manejo médico de acuerdo con la epidemiología local y las condiciones del paciente.

Tuberculosis is still a global public health burden. Infection caused by the bacillus Mycobacterium tuberculosis (M. Tuberculosis) manifests mainly in the lungs. However, around 20 % of cases occur in other anatomical locations and only 2 % have upper respiratory tract involvement. We present the case of a 75-year-old female patient, who returned to the otorhinolaryngology service due to epistaxis and postillomous lesions in the nasal cavity with a finding of a nasal mass. After surgical resection of the lesion, microbiological confirmation of M. tuberculosis infection is achieved. Studies are performed to rule-out lung involvement, as well as other locations. After the initiation of tuberculosis treatment, complete resolution of the lesion and no recurrence of symptoms is documented. Extrapulmonary forms of M. tuberculosis infection, and especially those involving the head and neck region, require a high index of suspicion for their diagnosis. Diagnostic methods such as PCR testing and tissue cultures allow optimal initiation of medical management according to local epidemiology and patient conditions.

A tuberculose ainda é um problema de saúde pública global. A infecção causada pelo Mycobacterium tuberculoses manifesta-se principalmente nos pulmões. Entretanto, cerca de 20% dos casos ocorrem em outras localizações anatômicas e apenas 2% apresentam comprometimento do trato respiratório superior. É apresentado o caso de uma mulher de 75 anos que retornou ao serviço de otorrinolaringologia por quadro de epistaxe, lesões com crostas em cavidade nasal e descoberta de massa nasal. Após ressecção cirúrgica da lesão, foi realizada verificação microbiológica de infecção por M. tuberculoses. Estudos são realizados para descartar envolvimento pulmonar e otras localizações. Após início do tratamento antituberculoso, houve resolução completa dalesão e não houve recidiva dos sintomas. As formas extrapulmonares da infecção por M. tuberculoses, especialmente aquelas que acometem a região de cabeça e pescoço, requerem alto índice de suspeita para diagnóstico. Métodos de diagnóstico, como testes de PCR e culturas de tecidos, permitem o início ideal do tratamento médico de acordó com a epidemiologia local e as condições do paciente.

Folate deficiency modifies the risk of CIN3+ associated with DNA methylation levels: a nested case-control study from the ASCUS-COL trial.

PURPOSE: To our knowledge, there are very few studies evaluating if the levels of folate modify the risk of cervical intraepithelial neoplasia grade 2 and higher (CIN2+ and CIN3+) associated with the levels of HPV genome methylation, two cofactors related to single carbon metabolism and independently associated with cervical cancer in previous studies. We conducted a case-control study nested in a three-arm randomized clinical pragmatic trial (ASCUS-COL trial) to evaluate the risk of CIN3+ associated with methylation levels according to serum folate concentrations. METHODS: Cases (n = 155) were women with histologically confirmed CIN2+ (113 CIN2, 38 CIN3, and 4 SCC) and controls were age and follow-up time at diagnosis-matched women with histologically confirmed ≤ CIN1 (n = 155), selected from the 1122 hrHPV + women of this trial. The concentrations of serum folate were determined by the radioimmunoassay SimulTRAC-SNB-VitaminB12/Folate-RIAKit and the methylation levels by the S5 classifier. Stepwise logistic regression models were used to estimate the association between folate or methylation levels and CIN2+ or CIN3+. The joint effect of folate levels and methylation on the risk of CIN3+ was estimated using combinations of categorical stratifications. RESULTS: Folate levels were significantly lower in women with CIN3+ than in other diagnostic groups (p = 0.019). The risk of CIN3+ was eight times higher (OR 8.9, 95% CI 3.4-24.9) in women with folate deficiency and high methylation levels than in women with normal folate and high methylation levels (OR 1.4, 95% CI 0.4-4.6). CONCLUSION: High methylation and deficient folate independently increased the risk of CIN3+ while deficient folate combined with high methylation was associated with a substantially elevated risk of CIN3+.

Disruption Of Non-COVID-19 Health Care In Latin America During The Pandemic: Effects On Health, Lessons For Policy.

COVID-19 had severe direct and indirect effects on health and well-being in Latin America. To understand the extent to which disruptions among non-COVID-19-related health services affected population health, we used administrative data from the period 2015-21 to examine public hospital discharges and mortality for conditions amenable to health care in four Latin American countries: Brazil, Ecuador, Mexico, and Peru. Between March 2020 and December 2021, hospitalization rates for these conditions declined by 28 percent and mortality rates increased by 15 percent relative to prepandemic years. Noncommunicable diseases accounted for 89 percent of this rise in mortality. The poorest states in each country experienced relatively larger increases in mortality. Our results, which focus on the health effects of service disruption, suggest that maintaining health care services in this region during the pandemic could have avoided at least 96,000 deaths. Policies should focus on maintaining essential health care services during emergencies, particularly for patients with noncommunicable diseases, and on minimizing negative consequences by ensuring coordinated and continuous care; leveraging alternative modalities of care, such as telemedicine; broadening the role of nonphysician health care workers; and expanding options for medication delivery.

miRNAs signature as potential biomarkers for cervical precancerous lesions in human papillomavirus positive women.

Biomarkers to identify women at risk of cervical cancer among those with high-risk HPV infection (hrHPV+) are needed. Deregulated expression of microRNAs (miRNAs) contributes to hrHPV-induced cervical carcinogenesis. We aimed at identifying miRNAs with the capacity to distinguish high (CIN2+) and low (≤ CIN1) grade cervical lesions. We sequenced miRNA libraries from Formalin-Fixed Paraffin-Embedded (FFPE) tissues from women with CIN2+ (n = 10) and age-matched women with ≤ CIN1 (n = 10), randomly and retrospectively selected from a trial that followed women for 24 months after a hrHPV+ test at the screening visit. Five miRNAs differentially expressed were validated by RT-qPCR in an independent set of FFPE tissues with a reviewed diagnosis of CIN2+ (n = 105) and ≤ CIN1 (n = 105). The Ingenuity Pathway Analysis (IPA) was conducted to identify mRNAs inversely correlated with the top 25 differentially expressed miRNAs. Inverse correlations with 401 unique mRNA targets were identified for fourteen of the top 25 differentially expressed miRNAs. Eleven of these miRNAs targeted 26 proteins of pathways deregulated by HPV E6 and E7 oncoproteins and two of them, miR-143-5p and miR-29a-3p, predicted CIN2+ and CIN3+ in the independent validation by RT-qPCR of FFPE tissues from hrHPV-positive women.

A phenomenological-based model of the endometrial growth and shedding during the menstrual cycle.

The human endometrium presents a remarkable growth dynamic with an outstanding regenerative capacity. This work aims to develop a phenomenological-based dynamic model to predict the volume changes in the functional layer of the endometrium in each phase of the menstrual cycle. This model considers changes in the endometrial tissue, the blood flow through the spiral arteries, the shedding of the endometrial cells, and the menstrual blood flow. The input variables are estrogen and progesterone; these hormone dynamics are taken from a pre-existing and validated model. Key parameters are modified in order to know their effect on the state variables. The model response was quantitatively assessed using the experimental data of the endometrial cycle reported in the literature. The proposed model provides a better insight into the interactions between ovarian hormones and the endometrial cycle by coupling both physiological processes.

Highly sensitive scent-detection of COVID-19 patients in vivo by trained dogs.

Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10-12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate, with 95.2% accuracy and high sensitivity (95.9%; 95% C.I. 93.6-97.4), specificity (95.1%; 94.4-95.8), positive predictive value (69.7%; 65.9-73.2), and negative predictive value (99.5%; 99.2-99.7) in relation to rRT-PCR. Seventy-five days after finishing in vivo efficacy experiments, a real-life study (in vivo effectiveness) was executed among the riders of the Metro System of Medellin, deploying the human-canine teams without previous training or announcement. Three dogs were used to examine the scent of 550 volunteers who agreed to participate, both in test with canines and in rRT-PCR testing. Negative predictive value remained at 99.0% (95% C.I. 98.3-99.4), but positive predictive value dropped to 28.2% (95% C.I. 21.1-36.7). Canine scent-detection in vivo is a highly accurate screening test for COVID-19, and it detects more than 99% of infected individuals independent of key variables, such as disease prevalence, time post-exposure, or presence of symptoms. Additional training is required to teach the dogs to ignore odoriferous contamination under real-life conditions.

Effective methylation triage of HPV positive women with abnormal cytology in a middle-income country.

The S5-methylation test, an alternative to cytology and HPV16/18 genotyping to triage high-risk HPV-positive (hrHPV+) women, has not been widely validated in low-middle-income countries (LMICs). We compared S5 to HPV16/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier-borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183

Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial.

In the context of opportunistic cervical cancer screening settings of low-and-middle-income countries, little is known about the benefits of high-risk human papillomavirus (hrHPV) testing on high-grade cervical abnormality detection among women with atypical squamous cells of undetermined significance (ASC-US) cytology in routine clinical practice. We compared the effectiveness of immediate colposcopy (IC), conventional cytology at 6 and 12 months (colposcopy if ≥ASC-US) (RC), and hrHPV testing (colposcopy if hrHPV-positive) (HPV) to detect cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) among women aged 20-69 years with ASC-US in routine care. Participants (n=2,661) were evenly randomized into three arms (n=882 IC, n=890 RC, n=889 HPV) to receive services by routine healthcare providers and invited to an exit visit 24 months after recruitment. Histopathology was blindly reviewed by a quality-control external panel (QC). The primary endpoint was the first QC-diagnosed CIN2+ or CIN3+ detected during three periods: enrolment (≤6 months for IC and HPV, ≤12 months for RC), follow-up (between enrolment and exit visit), and exit visit. The trial is completed. Colposcopy was done on 88%, 42%, and 52% of participants in IC, RC, and HPV. Overall, 212 CIN2+ and 52 CIN3+ cases were diagnosed. No differences were observed for CIN2+ detection (p=0.821). However, compared to IC, only HPV significantly reduced CIN3+ cases that providers were unable to detect during the 2-year routine follow-up (relative proportion 0.35, 95% CI 0.09-0.87). In this context, hrHPV testing was the most effective and efficient management strategy for women with ASC-US cytology.

Investigation of Porous Metal-Based 3D-Printed Anode GDLs for Tubular High Temperature Proton Exchange Membrane Fuel Cells.

A high-temperature proton exchange membrane fuel cell (HT-PEMFC) conventionally uses a planar design with carbon-based substrates as the gas diffusion layer (GDL) materials. However, the metal-based substrates allow for alternative designs. In this study, the applicability of porous thin-walled tubular elements made of 316L stainless steel as the anode GDL in a multi-layer tubular HT-PEMFC was investigated. The anode GDLs were fabricated via powder bed fusion using a laser beam (PBF-LB) process with defined porosities (14% and 16%). The morphology of the porous elements was compared using scanning electron microscopy (SEM) micrographs. The influence of the porosity on the fuel cell performance was evaluated through electrochemical characterization and a short-term stability test (45 h) in a commercial test station operated at 160 °C and ambient pressure, using hydrogen as the fuel and air as the oxidant. The results showed that the fuel cell manufactured upon the anode GDL with a porosity of 16% had a higher performance with a peak power density of 329.25 W/m2 after 5 h of operation at 125.52 A/m2 and a voltage degradation rate of 0.511 mV/h over the stability test period. Moreover, this work indicates that additive manufacturing could be a useful tool for further fuel cell development.

Nontherapeutic equivalence of a generic product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin.

BACKGROUND: We demonstrated therapeutic nonequivalence of "bioequivalent" generics for meropenem, but there is no data with generics of other carbapenems. METHODS: One generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS). RESULTS AND CONCLUSION: The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.

Diffuse alveolar hemorrhage syndrome secondary to bocavirus and rhinovirus infection in a pediatric patient / Síndrome de hemorragia alveolar difusa secundaria a coinfección por Rhinovirus y Bocavirus en un paciente pediátrico

Abstract The diffuse alveolar hemorrhage syndrome is characterized by the presence of blood in the pulmonary alveolus from arterioles, venules and pulmonary capillaries, as a consequence of the lesion of the alveolar wall and without an endobronchial alteration. Its presentation includes a classic triad of hemoptysis, anemia and diffuse alveolar infiltrates. It's a rare but potentially fatal entity and there are no clear data on its real incidence in the pediatric population. We present the case of a previously healthy pediatric patient, immunocompetent, who presented diffuse alveolar hemorrhage syndrome with secondary ventilatory failure. After discarding all possible etiologies, coinfection by Rhinovirus and human Bocavirus was detected through the polymerase chain reaction, determining them as causal factors of the event. Recently, viral infections have been postulated as causing serious lung disease, especially coinfection in immunocompromised patients, in this case Rhinovirus and human Bocavirus; however there are no reports on the syndrome caused by these viruses.

Resumen El síndrome de hemorragia alveolar difusa se caracteriza por la presencia de sangre los alveolos pulmonar procedente de arteriolas, vénulas y capilares pulmonares, como consecuencia de la lesión de la pared alveolar y sin identificársele una alteración endobronquial. Su presentación incluye una triada clásica de hemoptisis, anemia e infiltrados alveolares difusos. Es una entidad poco frecuente aunque potencialmente fatal y no hay datos claros de su real incidencia en la población pediátrica. Se presenta el caso de un paciente pediátrico previamente sano, inmunocompetente, quien presentó síndrome de hemorragia alveolar difusa con falla ventilatoria secundaria. Después de descartar todas las posibles etiologías, se detectó, a través de reacción en cadena de polimerasa, coinfeccion por Rhinovirus y Bocavirus humano, determinándolos como causales del evento. Recientemente se postula las infecciones virales como causantes de enfermedad pulmonar grave, en especial la coinfeccion en pacientes inmunocomprometidos, en este caso Rhinovirus y Bocavirus humano, sin embargo no existen reportes sobre el síndrome causada por estos virus.

Hepatoblastoma: Transplant Versus Resection Experience in a Latin American Transplant Center.

BACKGROUND: Hepatoblastoma is the most common primary malignant liver tumor in children and is usually diagnosed during the first 3 years of life. Overall survival has increased 50% due to chemotherapeutic schemes, expertise surgery centers, and liver transplantation. METHODS: A retrospective collection of data was performed from pediatric patients with diagnosis of hepatoblastoma. Variables included demographic, diagnostic tools and histological classification; chemotherapy and surgical treatment; and outcomes and patient survival. The PRETEXT classification was applied, which included the risk evaluation, and according to the medical criterion in an individualized way, underwent resection or transplant. The morbidity of patients was evaluated by the Clavien-Dindo classification. Statistical analysis was performed according to the distribution of data and the survival analysis was carried out using the Kaplan-Meier method. RESULTS: The patients (n = 16) were divided in a resection group (n = 8) and a transplant group (n = 8). The median age at the time of diagnosis was 13.5 months. The motive for the initial consultation was the discovery of a mass; all patients had high levels of α-fetoprotein and an imaging study. Ten of 16 patients required chemotherapy before the surgical procedure. In the resection group, 5 of 8 patients were classified as Clavien I and 4 of 8 patients of the transplant group were classified as Clavien II. Patient survival at 30 months was 100% in the resection group and 65% in the liver transplantation group. CONCLUSIONS: To our knowledge, this is the first case report of pediatric patients with hepatoblastoma and liver resection or transplant in Colombia and Latin America. Our results are comparable with the series worldwide, showing that resection and transplant increase the survival of the pediatric patients with hepatoblastoma. It is important to advocate for an increase of reporting in the scientific literature in Latin America.

The situation of nursing education in Latin America and the Caribbean towards universal health.

OBJECTIVE:: to assess the situation of nursing education and to analyze the extent to which baccalaureate level nursing education programs in Latin America and the Caribbean are preparing graduates to contribute to the achievement of Universal Health. METHOD:: quantitative, descriptive/exploratory, cross-sectional study carried out in 25 countries. RESULTS:: a total of 246 nursing schools participated in the study. Faculty with doctoral level degrees totaled 31.3%, without Brazil this is reduced to 8.3%. The ratio of clinical experiences in primary health care services to hospital-based services was 0.63, indicating that students receive more clinical experiences in hospital settings. The results suggested a need for improvement in internet access; information technology; accessibility for the disabled; program, faculty and student evaluation; and teaching/learning methods. CONCLUSION:: there is heterogeneity in nursing education in Latin America and the Caribbean. The nursing curricula generally includes the principles and values of Universal Health and primary health care, as well as those principles underpinning transformative education modalities such as critical and complex thinking development, problem-solving, evidence-based clinical decision-making, and lifelong learning. However, there is a need to promote a paradigm shift in nursing education to include more training in primary health care. OBJETIVO:: avaliar a situação da educação em enfermagem e analisar o quanto os programas de educação em enfermagem, no nível de Bacharelado na América Latina e no Caribe, estão preparando graduados a contribuir para o alcance da Saúde Universal. MÉTODO:: estudo quantitativo, descritivo/exploratório, transversal, realizado em 25 países. RESULTADOS:: um total de 246 escolas de enfermagem participaram do estudo. O corpo docente com nível de Doutorado totalizou 31,3%; sem o Brasil o número fica reduzido a 8,3%. A razão entre experiências clínicas nos serviços de atenção primária à saúde e nos serviços hospitalares foi de 0,63, indicando que os estudantes têm mais experiências clínicas nos cenários hospitalares. Os resultados sugeriram necessidade de aprimoramento relacionada ao acesso à Internet; tecnologia da informação; acesso para portadores de deficiências; avaliação do programa, do corpo docente e dos estudantes; e aos métodos de ensino/aprendizagem. CONCLUSÃO:: há heterogeneidade na educação em enfermagem na América Latina e no Caribe. Os currículos de enfermagem incluem, geralmente, os princípios e valores da Saúde Universal e da atenção primária à saúde, bem como aqueles princípios subjacentes às modalidades de educação transformativa, como o desenvolvimento de pensamento crítico e complexo, a solução de problemas, a tomada de decisão clínica baseada em evidências, e aprendizagem contínua. No entanto, é preciso promover uma mudança de paradigma na educação em enfermagem que inclua mais treinamento na atenção primária à saúde. OBJETIVO:: evaluar la situación de la educación en enfermería y analizar en qué grado los programas de educación de enfermería a nivel de grado en América Latina y el Caribe están preparando a los graduados para contribuir al logro de la Salud Universal. MÉTODO:: se llevó a cabo un estudio transversal, cuantitativo, descriptivo y exploratorio en 25 países. RESULTADOS:: participaron en el estudio 246 escuelas de enfermería. El porcentaje de profesores con títulos de doctorado fue de 31,3%; pero, si se excluye a Brasil esta cifra se reduce a 8,3%. La proporción de la experiencia clínica adquirida en los servicios de atención primaria de salud en relación con la adquirida en servicios hospitalarios fue de 0,63, lo que indica que los estudiantes adquieren la mayor parte de su experiencia clínica en entornos hospitalarios. Los resultados mostraron una necesidad de mejorar el acceso a internet; la tecnología de la información; la accesibilidad para las personas discapacitadas; la evaluación de los programas, de los profesores y de los estudiantes; y los métodos de enseñanza y aprendizaje. CONCLUSIONES:: hay heterogeneidad en la educación en enfermería en América Latina y el Caribe. En general, los programas de estudios de enfermería han adoptado los principios y los valores de la Salud Universal y la atención primaria de salud, así como los principios que sustentan las modalidades de educación transformadora, como son el desarrollo del pensamiento crítico y complejo, la solución de problemas, la toma de decisiones clínicas basadas en la evidencia y el aprendizaje a lo largo de toda la vida. Sin embargo, hay necesidad de promover un cambio en el paradigma de la educación en enfermería, a fin de que abarque más capacitación en la atención primaria de salud.

PPD-induced monocyte mitochondrial damage is associated with a protective effect to develop tuberculosis in BCG vaccinated individuals: A cohort study.

INTRODUCTION: The mechanisms of mononuclear phagocyte death have been associated with the permissiveness and resistance to mycobacterial replication, but it remains unknown whether or not they help predict the risk of developing TB. OBJECTIVE: To describe the factors associated with the induction of monocyte mitochondrial and membrane damage in response to PPD as well as determine if this type of damage might predict the susceptibility of developing active tuberculosis in a cohort of household contacts (HHCs) from Medellin, Colombia from 2005 to 2008. METHODS: The prospective cohort study contains 2060 HHCs patients with pulmonary tuberculosis who were meticulously followed for two years. A survey of the socio-demographic, clinical, epidemiological factors and blood samples were collected. Mononuclear cell cultures were stimulated with or without PPD and the type of monocyte death was determined by the flow of cytometry, an indicator was also used for its analysis. Logistic regression was adjusted by the Generalized Estimations Equations and the survival was estimated with the Kaplan-Meier and Cox regression. Confidence intervals were used for estimating the association. RESULTS: 1,859 out of 2,060 blood samples of the HHCs patients analyzed showed monocyte death. In response to PPD, 83.4% underwent mitochondrial damage while 50.9% had membrane damage. The membrane damage in response to PPD was higher in children under 4 years (OR: 1.57; (95% CI: 1.1 to 2.4) and the HHCs who slept regularly in the same household has an index case of (OR: 1.54; 95% CI: 1.0 to 2.3). After adjustment by age, comorbidities, nutritional status, proximity to index case and overcrowding, the risk of developing active TB among BCG vaccinated HHCs individuals with induction of mitochondrial damage was HR = 0.19 (95% CI: 0.1 to 0.5). CONCLUSIONS: The induction of monocytes mitochondrial damage by PPD stimulation correlates with protection of TB disease development in BCG-vaccinated HHCs. This represents a potential tool to predict susceptibility of developing active disease in this population.

Antifungal pharmacodynamics: Latin America's perspective

Abstract The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

In vivo pharmacodynamics of piperacillin/tazobactam: implications for antimicrobial efficacy and resistance suppression with innovator and generic products.

Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of ß-lactam/ß-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 ß-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10 kill. The non-equivalent generic required a longer exposure (fT>threshold 33%) to suppress resistance compared with the innovator (fT>threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence.

Antifungal pharmacodynamics: Latin America's perspective.

The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

The situation of nursing education in Latin America and the Caribbean towards universal health / A Situação da Educação em Enfermagem na América Latina e no Caribe Rumo à Saúde Universal / La situación de la educación en enfermería en América Latina y el Caribe hacia el logro de la salud universal

Objective: to assess the situation of nursing education and to analyze the extent to which baccalaureate level nursing education programs in Latin America and the Caribbean are preparing graduates to contribute to the achievement of Universal Health. Method: quantitative, descriptive/exploratory, cross-sectional study carried out in 25 countries. Results: a total of 246 nursing schools participated in the study. Faculty with doctoral level degrees totaled 31.3%, without Brazil this is reduced to 8.3%. The ratio of clinical experiences in primary health care services to hospital-based services was 0.63, indicating that students receive more clinical experiences in hospital settings. The results suggested a need for improvement in internet access; information technology; accessibility for the disabled; program, faculty and student evaluation; and teaching/learning methods. Conclusion: there is heterogeneity in nursing education in Latin America and the Caribbean. The nursing curricula generally includes the principles and values of Universal Health and primary health care, as well as those principles underpinning transformative education modalities such as critical and complex thinking development, problem-solving, evidence-based clinical decision-making, and lifelong learning. However, there is a need to promote a paradigm shift in nursing education to include more training in primary health care.

Objetivo: avaliar a situação da educação em enfermagem e analisar o quanto os programas de educação em enfermagem, no nível de Bacharelado na América Latina e no Caribe, estão preparando graduados a contribuir para o alcance da Saúde Universal. Método: estudo quantitativo, descritivo/exploratório, transversal, realizado em 25 países. Resultados: um total de 246 escolas de enfermagem participaram do estudo. O corpo docente com nível de Doutorado totalizou 31,3%; sem o Brasil o número fica reduzido a 8,3%. A razão entre experiências clínicas nos serviços de atenção primária à saúde e nos serviços hospitalares foi de 0,63, indicando que os estudantes têm mais experiências clínicas nos cenários hospitalares. Os resultados sugeriram necessidade de aprimoramento relacionada ao acesso à Internet; tecnologia da informação; acesso para portadores de deficiências; avaliação do programa, do corpo docente e dos estudantes; e aos métodos de ensino/aprendizagem. Conclusão: há heterogeneidade na educação em enfermagem na América Latina e no Caribe. Os currículos de enfermagem incluem, geralmente, os princípios e valores da Saúde Universal e da atenção primária à saúde, bem como aqueles princípios subjacentes às modalidades de educação transformativa, como o desenvolvimento de pensamento crítico e complexo, a solução de problemas, a tomada de decisão clínica baseada em evidências, e aprendizagem contínua. No entanto, é preciso promover uma mudança de paradigma na educação em enfermagem que inclua mais treinamento na atenção primária à saúde.

Objetivo: evaluar la situación de la educación en enfermería y analizar en qué grado los programas de educación de enfermería a nivel de grado en América Latina y el Caribe están preparando a los graduados para contribuir al logro de la Salud Universal. Método: se llevó a cabo un estudio transversal, cuantitativo, descriptivo y exploratorio en 25 países. Resultados: participaron en el estudio 246 escuelas de enfermería. El porcentaje de profesores con títulos de doctorado fue de 31,3%; pero, si se excluye a Brasil esta cifra se reduce a 8,3%. La proporción de la experiencia clínica adquirida en los servicios de atención primaria de salud en relación con la adquirida en servicios hospitalarios fue de 0,63, lo que indica que los estudiantes adquieren la mayor parte de su experiencia clínica en entornos hospitalarios. Los resultados mostraron una necesidad de mejorar el acceso a internet; la tecnología de la información; la accesibilidad para las personas discapacitadas; la evaluación de los programas, de los profesores y de los estudiantes; y los métodos de enseñanza y aprendizaje. Conclusiones: hay heterogeneidad en la educación en enfermería en América Latina y el Caribe. En general, los programas de estudios de enfermería han adoptado los principios y los valores de la Salud Universal y la atención primaria de salud, así como los principios que sustentan las modalidades de educación transformadora, como son el desarrollo del pensamiento crítico y complejo, la solución de problemas, la toma de decisiones clínicas basadas en la evidencia y el aprendizaje a lo largo de toda la vida. Sin embargo, hay necesidad de promover un cambio en el paradigma de la educación en enfermería, a fin de que abarque más capacitación en la atención primaria de salud.

Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics: The Case of Piperacillin-Tazobactam.

Previous studies have demonstrated that pharmaceutical equivalence and pharmacokinetic equivalence of generic antibiotics are necessary but not sufficient conditions to guarantee therapeutic equivalence (better called pharmacodynamic equivalence). In addition, there is scientific evidence suggesting a direct link between pharmacodynamic nonequivalence of generic vancomycin and promotion of resistance in Staphylococcus aureus. To find out if even subtle deviations from the expected pharmacodynamic behavior with respect to the innovator could favor resistance, we studied a generic product of piperacillin-tazobactam characterized by pharmaceutical and pharmacokinetic equivalence but a faulty fit of Hill's Emax sigmoid model that could be interpreted as pharmacodynamic nonequivalence. We determined the impact in vivo of this generic product on the resistance of a mixed Escherichia coli population composed of ∼99% susceptible cells (ATCC 35218 strain) and a ∼1% isogenic resistant subpopulation that overproduces TEM-1 ß-lactamase. After only 24 hours of treatment in the neutropenic murine thigh infection model, the generic amplified the resistant subpopulation up to 20-times compared with the innovator, following an inverted-U dose-response relationship. These findings highlight the critical role of therapeutic nonequivalence of generic antibiotics as a key factor contributing to the global problem of bacterial resistance.