Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior.

Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

Se Nanoparticles Induce Changes in the Growth, Antioxidant Responses, and Fruit Quality of Tomato Developed under NaCl Stress.

Nanotechnology represents an opportunity to improve the use of elements in agriculture. Selenium is an element that is beneficial to plants and essential to the human diet. The size of nanoparticles gives them characteristics that can enhance the benefits that selenium provides to plants. The objective of the present study was to determine the effects of selenium nanoparticles on the growth, antioxidant responses, and fruit quality of tomato developed under NaCl stress. Four doses of selenium nanoparticles (1, 5, 10, and 20 mg L-1) under NaCl stress, only NaCl, and a control were evaluated. The results showed that the impact of salinity on the growth of the tomato crop can be reduced with the application of selenium nanoparticles. However, the amount of both enzymatic and non-enzymatic compounds significantly increased in the leaves and fruits of tomato. The results suggest that the application of selenium nanoparticles generated a positive effect against salinity in the tomato crop; moreover, it had a positive impact on the content of beneficial biocompounds for human health in tomato fruits.

Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation.

Designer receptors exclusively activated by designer drug (DREADDs) are a novel tool with the potential to bidirectionally drive cellular, circuit, and ultimately, behavioral changes. We used DREADDs to evaluate memory formation in a hippocampus-dependent task in mice and effects on synaptic physiology in the dorsal hippocampus. We expressed neuron-specific (hSyn promoter) DREADDs that were either excitatory (HM3D) or inhibitory (HM4D) in the dorsal hippocampus. As predicted, hSyn-HM3D was able to transform a subthreshold learning event into long-term memory (LTM), and hSyn-HM4D completely impaired LTM formation. Surprisingly, the opposite was observed during experiments examining the effects on hippocampal long-term potentiation (LTP). hSyn-HM3D impaired LTP and hSyn-HM4D facilitated LTP. Follow-up experiments indicated that the hSyn-HM3D-mediated depression of fEPSP appears to be driven by presynaptic activation of inhibitory currents, whereas the hSyn-HM4D-mediated increase of fEPSP is induced by a reduction in GABAA receptor function. To determine whether these observations were promoter specific, we next examined the effects of using the CaMKIIα promoter that limits expression to forebrain excitatory neurons. CaMKIIα-HM3D in the dorsal hippocampus led to the transformation of a subthreshold learning event into LTM, whereas CaMKIIα-HM4D blocked LTM formation. Consistent with these findings, baseline synaptic transmission and LTP was increased in CaMKIIα-HM3D hippocampal slices, whereas slices from CaMKIIα-HM4D mice produced expected decreases in baseline synaptic transmission and LTP. Together, these experiments further demonstrate DREADDs as being a robust and reliable means of modulating neuronal function to manipulate long-term changes in behavior, while providing evidence for specific dissociations between LTM and LTP. SIGNIFICANCE STATEMENT: This study evaluates the efficacy of designer receptors exclusively activated by designer drug (DREADDs) as a means of bidirectionally modulating the hippocampus in not only a hippocampus-dependent task but also in hippocampal synaptic plasticity. This is the first study to evaluate the effects of DREADD-mediated inhibition and excitation in hippocampal long-term potentiation. More specifically, this study evaluates the effect of promoter-specific expression of DREADD viruses in a heterogenic cell population, which revealed surprising effects of different promoters. With chemogenetics becoming a more ubiquitous tool throughout studies investigating circuit-specific function, these data are of broad interest to the neuroscientific community because we have shown that promoter-specific effects can drastically alter synaptic function within a specific region, without parallel changes at the level of behavior.

[Concept frame for curricular innovation in health care schools]. / Desarrollo de una matriz conceptual para la innovación curricular en profesiones de la salud.

We herein describe the conceptual dimension of the curricular innovation process carried out in the Faculty of Medicine of the University of Chile. We describe the context of innovation. The theoretical pertinence and relevance of a competence driven curriculum for health care professionals is discussed. The epistemological, ontological and didactic dimensions of the curricular innovation are examined. A main issue is the notion of competence and its significance in professional training. The curriculum is essentially considered as a moral endeavor, especially for health care professionals and their quest to improve the quality of life of the population.

[The educational change in medical schools]. / Cambio educativo en las Facultades de Medicina.

This paper reports the reflections of a group of members of the University of Chile Faculty of Medicine, about the changes in teaching methods that medical schools should incorporate. In a complex scenario, not only new and better knowledge should be transmitted to students but also values, principles, critical reasoning and leadership, among others. In the first part, a proposal to understand this educational development in the context of complex universities, incorporating pedagogical skills and reviewing institutional leadership, is carried out. In the second part, the training of teaching physicians, as part of the changes, is extensively discussed. Physicians hired as academics in the University should have the opportunity to work mainly as teachers and be relieved of research obligations. For them, teaching should become a legitimate area of academic development.

Efficacy and safety of sitagliptin with basal-plus insulin regimen versus insulin alone in non-critically ill hospitalized patients with type 2 diabetes: SITA-PLUS hospital trial.

AIMS: To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D). METHODS: This open-label, randomized clinical trial included inpatients with a previous diagnosis of T2D and blood glucose (BG) between 180 and 400 mg/dL. Participants received basal and correctional insulin doses (BP regimen) either with or without sitagliptin. The primary outcome was the difference in the mean daily BG among the groups. RESULTS: Seventy-six patients (mean age 60 years, 64 % men) were randomized. Compared with BP insulin therapy alone, the sitagliptin-BP combination led to a lower mean daily BG (158.8 vs 175.0 mg/dL, P = 0.014), a higher percentage of readings within a BG range of 70-180 mg/dL (75.9 % vs 64.7 %, P < 0.001), and a lower number of BG readings >180 mg/dL (P < 0.001). Sitagliptin-BP resulted in fewer basal and supplementary insulin doses (P = 0.024 and P = 0.017, respectively) and lower daily insulin injections (P = 0.023) than those with insulin alone. The proportion of patients with hypoglycemia was similar in the two groups. CONCLUSIONS: For inpatients with T2D and hyperglycemia, the sitagliptin and BP regimen combination is safe and more effective than insulin therapy alone. CLINICALTRIALS: gov identifier: NCT05579119.

A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma.

PURPOSE: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). PATIENTS AND METHODS: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. RESULTS: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. CONCLUSIONS: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.

Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin.

OBJECTIVE: Systemic sclerosis (SSc) patients are classified according to degree of skin fibrosis (limited and diffuse cutaneous [lc and dc]) and serum autoantibodies. We undertook the present multicenter study to determine whether intrinsic subset (IS) classification based upon skin gene expression yields additional valuable clinical information. METHODS: SSc patients and healthy participants (HPs) were classified into Normal-like, Limited, Fibroproliferative, and Inflammatory ISs using a previously trained classifier. Clinical data were obtained (serum autoantibodies, pulmonary function testing, modified Rodnan skin thickness scores [mRSS], and high-resolution chest computed tomography [HRCT]). Statistical analyses were performed to compare patients classified by IS, traditional cutaneous classification, and serum autoantibodies. RESULTS: A total of 223 participants (165 SSc [115 dcSSc and 50 lcSSc] and 58 HPs) were classified. Inflammatory IS patients had higher mRSS (22.1 ± 9.9; P < 0.001) than other ISs and dcSSc patients (19.4 ± 9.4; P = 0.05) despite similar disease duration (median [interquartile range] months 14.9 [19.9] vs. 18.4 [31.6]; P = 0.48). In multivariable modeling, no significant association between mRSS and RNA polymerase III (P = 0.07) or anti-topoisomerase I (Scl-70) (P = 0.09) was found. Radiographic interstitial lung disease (ILD) was more prevalent in Fibroproliferative IS compared with other ISs (91%; P = 0.04) with similar prevalence between lcSSc and dcSSc (67% vs. 76%; P = 0.73). Positive Scl-70 antibody was the strongest ILD predictor (P < 0.001). Interestingly, all lcSSc/Fibroproliferative patients demonstrated radiographic ILD. CONCLUSIONS: Classification by IS identifies patients with distinct clinical phenotypes versus traditional cutaneous or autoantibody classification. IS classification identifies subgroups of SSc patients with more radiographic ILD (Fibroproliferative), higher mRSS (Inflammatory), and milder phenotype (Normal-like) and may provide additional clinically useful information to current SSc classification systems.

Machine-learning classification identifies patients with early systemic sclerosis as abatacept responders via CD28 pathway modulation.

Here, the efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic subset would show the most significant clinical improvement. Eighty-four participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-Seq was performed on 233 skin paired biopsies at baseline and at 3 and 6 months. Improvement was defined as a 5-point or more than 20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subsets (inflammatory, fibroproliferative, or normal-like subsets). In the abatacept arm, change in mRSS was most pronounced for the inflammatory and normal-like subsets relative to the placebo subset. Gene expression for participants on placebo remained in the original molecular subset, whereas inflammatory participants treated with abatacept had gene expression that moved toward the normal-like subset. The Costimulation of the CD28 Family Reactome Pathway decreased in patients who improved on abatacept and was specific to the inflammatory subset. Patients in the inflammatory subset had elevation of the Costimulation of the CD28 Family pathway at baseline relative to that of participants in the fibroproliferative and normal-like subsets. There was a correlation between improved ΔmRSS and baseline expression of the Costimulation of the CD28 Family pathway. This study provides an example of precision medicine in systemic sclerosis clinical trials.

Molecular "omic" signatures in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by immunologic, vascular, and extracellular matrix abnormalities. Variation in the proportion and/or timing of activation in the deregulated molecular pathways that underlie SSc may explain the observed clinical heterogeneity in terms of disease phenotype and treatment response. In recent years, SSc research has generated massive amounts of "omics" level data. In this review, we discuss the body of "omics" level work in SSc and how each layer provides unique insight to our understanding of SSc. We posit that effective integration of genomic, transcriptomic, metagenomic, and epigenomic data is an important step toward precision medicine and is vital to the identification of effective therapeutic options for patients with SSc.

Parent reported outcomes to measure satisfaction, acceptability, and daily life impact after vaccination with whole-cell and acellular pertussis vaccine in Chile.

AIM: To compare parental satisfaction and impact on daily life among parents of children receiving whole-cell pentavalent + oral polio vaccine (Arm1) with an acellular hexavalent vaccine (Hexaxim; Arm2). METHODS: Self-administered electronic questionnaire at vaccination and one week later in six community health clinics of metropolitan Santiago, Chile, exploring parent-reported outcomes on satisfaction, acceptability, and impact on daily life after immunization. Univariate and multivariate analyses were conducted to determine differences in the responses in both groups (α = 0.05). RESULTS: The study enrolled 800 participants and 65% (222 in Arm1, 296 in Arm2) were included for according-to-protocol analysis. Demographic characteristics were comparable, except for a higher proportion of mothers answering the questionnaire at the 6-month visit. Regardless of the study arm, parental knowledge and perception of the immunization practices were good, and there were no differences in vaccination experiences in the prior 5 years. However, satisfaction with vaccination and intention to vaccinate were statistically significantly higher in Arm2 after the 6-month visit. Also, more parents in Arm2 reported no disruption in several aspects of the everyday activities of the parent, the child, and other children in the household. Parents in Arm2 were more likely to be satisfied with the vaccine received (OR 2.82; 95% CI, 1.22-7.07); return for other vaccine dose (OR 2.62; 95% CI, 1.45-4.84); follow a healthcare professional recommendation (OR 2.24; 95% CI, 1.57-3.21); and, to be confident that the vaccine will not disrupt the family's daily routine (OR 1.89; 95% CI, 1.32-2.71). CONCLUSIONS: Overall, satisfaction, intention for future vaccination, and lower impact on the family daily routine were significantly better in the group receiving the hexavalent vaccine. We also found that health care providers' recommendations to vaccinate and participants' access to health services were important factors favoring immunization.

Norovirus compared to other relevant etiologies of acute gastroenteritis among families from a semirural county in Chile.

OBJECTIVE: To determine the dynamics of norovirus disease, a major cause of acute gastroenteritis (AGE), compared to other relevant etiologies, among families living in a lower middle income area. STUDY DESIGN: Families with three or more members and with one or more healthy children <24 months of age were followed for 1-2 years to detect any AGE. Stool samples were tested for viral and bacterial pathogens and a questionnaire was completed for those with norovirus or rotavirus AGE. RESULTS: Between April and June 2016, 110 families were enrolled, with 103 of them completing ≥12 months of follow-up. A total of 159 family AGE episodes were detected, mostly affecting one individual (92%). At least one pathogen was detected in 56% (94/169) of samples, of which 75/94 (80%) were sole infections. Norovirus was most common (n=26), followed closely by enteropathogenic Escherichia coli (EPEC) (n=25), rotavirus (n=24), and astrovirus (n=23). The annual incidence of family AGE was 0.77, and 0.12 for norovirus. Most norovirus AGE occurred in children <4 years old (96%). Only 13/159 (8%) index AGE cases resulted in a secondary case, of which four were associated with norovirus. The majority of norovirus strains were GII (85%), with a mild predominance of GII.4 (9/26; 35%); most norovirus isolates (69%) were recombinants. CONCLUSIONS: The family incidence of AGE in this lower middle income community was nearly one episode per year, mostly caused by viruses, specifically norovirus closely followed by rotavirus and astrovirus. Norovirus infections primarily affected children <4 years old and secondary cases were uncommon.

Determination of reactions between free radicals and selected Chilean wines and transition metals by ESR and UV-vis technique.

Four different types of Chilean wines (Cabernet Sauvignon, Merlot, Carmenere and Syrah) were selected and examined in their free radical scavenging capacities by electron spin resonance (ESR) and spectrophotometric methods. The free radical scavenging properties were evaluated against 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical, 2,6-di-tert-butyl-alpha-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-p-tolyloxy (Galvinoxyl) radical and hydroxyl radical (HO*). The possible effect on these scavenging properties of added transition metals to these wines was evaluated. Among the wines evaluated, Cabernet Sauvignon was the one with the highest activity against all radicals tested. The presence of added copper or iron to wines resulted in a reduced free radical scavenging capacity for all type of wines studied. The formation of redox inactive complexes between polyphenols of wine and transition metals is the possible cause of this reduction in antioxidant activity.

[Usefulness of the determination of IgG and IgM antibodies by ELISA and immunocapture in a clinical series of human brucellosis]. / Utilidad de la determinación de anticuerpos IgG e IgM por ELISA e inmunocaptura en una serie clínica de brucelosis humana.

INTRODUCTION: The diagnostic difficulties of brucellosis makes the evaluation of new diagnostic tests necessary. OBJECTIVES: Evaluation of different commercial tests in the serological diagnosis of brucellosis by ELISA and immunocapture antibodies in a clinical series of patients with brucellosis of the Health Network of the Catholic University of Chile. METHODS: All the serums received in the Laboratory of Microbiology for suspicion of brucellosis during five years were studied. Two groups were obtained, one that fulfilled diagnostic criteria for brucellosis [clinical evidence, and/or positive blood culture and/or seroagglutination test (SAT) in titers > 1/160] and the control group. Each serum sample was analyzed using irnmunocapture-agglutination test (Brucellacapt), ELISA IgM and IgG. RESULTS: Of 10 patients with brucellosis, the serologic results were: 8/10 positives for ELISA IgG, 7/10 for Brucellacapt and SAT, and 5/10 for ELISA IgM. DISCUSSION: ELISA IgG alone was superior than SAT. The combination ELISA IgG/ Brucellacapt reaches the best detection performance (9/10) and can be an alternative to SAT.

Cambios en la cobertura del matorral seco montano del valle Chota (Imbabura y Carchi, Ecuador) entre 1990 y 2020

El cambio en el uso del suelo es uno de los principales conductores del cambio global, así como una causa de la pérdida de biodiversidad. En el norte del Ecuador, el matorral seco montano es un ecosistema característico de los valles interandinos y que se encuentra amenazado por la intervención antrópica. El presente trabajo estudió el cambio de la cobertura del matorral seco montano en el valle del río Chota en un periodo de 30 años y evaluó su estado de conservación. Se aplicó el método de clasificación supervisada en las imágenes satelitales LANDSAT de los años 1990, 2007 y 2020, para analizar las tasas de variación de las coberturas. El estado de conservación se determinó con una matriz de evaluación que consideró siete variables y 25 indicadores y la sobreposición de capas temáticas con SIG. Los resultados denotaron una pérdida del 20% de la cobertura del matorral seco montano, a un promedio anual de 231.83 ha/año (-0.75%) por causas antrópicas. Estas causas fueron responsables del cambio de cobertura de más de la mitad del 8.34% del área que ocupaba, principalmente la expansión de la frontera agrícola con un 3.96%. La presión y efecto de los factores antrópicos identificados causaron que el estado actual de conservación sea Regular. Se proponen tres estrategias de conservación: buenas prácticas agroecológicas, una gestión ambiental integral y la educación ambiental.

Land use change is one of the main drivers of global change, as well as a cause of biodiversity loss. In northern Ecuador, the montane dry scrub is a characteristic ecosystem of the inter-Andean valleys and is threatened by anthropogenic intervention. This study examined the change in montane dry scrub coverage in the Chota River Valley over a 30-year period and evaluated its conservation status. The supervised classification method was applied to LANDSAT satellite images from 1990, 2007, and 2020 to analyze the rates of coverage variation. The conservation status was determined using an evaluation matrix that considered seven variables and 25 indicators and the overlap of thematic layers with GIS. The results showed a loss of 20% of montane dry scrub coverage, at an annual average of 231.83 ha/year (-0.75%) due to anthropogenic causes. These causes were responsible for the coverage change of more than half of the 8.34% of the area it occupied, mainly the expansion of the agricultural frontier with 3.96%. The pressure and effect of the identified anthropogenic factors caused the current conservation status to be Regular. Three conservation strategies are proposed: good agroecological practices, comprehensive environmental management, and environmental education.

Differential signalling for enhanced hexose uptake by interleukin (IL)-3 and IL-5 in male germ cells.

We studied the expression and function of the IL (interleukin)-3 and IL-5 family of receptors in male germ cells. RT (reverse transcription)-PCR showed expression of mRNAs encoding the alpha and beta subunits of the IL-3 and IL-5 receptors in human testis, and the presence of IL-3 and IL-5 receptors alpha and beta proteins was confirmed by immunoblotting with anti-alpha and anti-beta antibodies. The immunolocalization studies showed expression of these receptors in the germ line in the human testis and in human and bovine ejaculated spermatozoa. Functional studies with bull spermatozoa indicated that IL-3 signalled for increased uptake of hexoses in these cells at picomolar concentrations compatible with expression of functional high-affinity IL-3 receptors in these cells. In contrast, IL-5 failed to induce increased hexose uptake in bull spermatozoa. Experiments using HL-60 eosinophils that express functional IL-3 and IL-5 receptors confirmed that IL-3, but not IL-5, signalled for increased hexose uptake. Our findings suggest that differential signalling for increased hexose uptake by heteromeric high-affinity IL-3 and IL-5 receptors in mammalian spermatozoa is a property that depends on the identity of the alpha-subunit forming part of the alphabeta-complex and is not a property specific to the germ cells.

Inactivated poliovirus vaccine given alone or in a sequential schedule with bivalent oral poliovirus vaccine in Chilean infants: a randomised, controlled, open-label, phase 4, non-inferiority study.

BACKGROUND: Bivalent oral poliovirus vaccine (bOPV; types 1 and 3) is expected to replace trivalent OPV (tOPV) globally by April, 2016, preceded by the introduction of at least one dose of inactivated poliovirus vaccine (IPV) in routine immunisation programmes to eliminate vaccine-associated or vaccine-derived poliomyelitis from serotype 2 poliovirus. Because data are needed on sequential IPV-bOPV schedules, we assessed the immunogenicity of two different IPV-bOPV schedules compared with an all-IPV schedule in infants. METHODS: We did a randomised, controlled, open-label, non-inferiority trial with healthy, full-term (>2·5 kg birthweight) infants aged 8 weeks (± 7 days) at six well-child clinics in Santiago, Chile. We used supplied lists to randomly assign infants (1:1:1) to receive three polio vaccinations (IPV by injection or bOPV as oral drops) at age 8, 16, and 24 weeks in one of three sequential schedules: IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV. We did the randomisation with blocks of 12 stratified by study site. All analyses were done in a masked manner. Co-primary outcomes were non-inferiority of the bOPV-containing schedules compared with the all-IPV schedule for seroconversion (within a 10% margin) and antibody titres (within two-thirds log2 titres) to poliovirus serotypes 1 and 3 at age 28 weeks, analysed in the per-protocol population. Secondary outcomes were seroconversion and titres to serotype 2 and faecal shedding for 4 weeks after a monovalent OPV type 2 challenge at age 28 weeks. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01841671, and is closed to new participants. FINDINGS: Between April 25 and August 1, 2013, we assigned 570 infants to treatment: 190 to IPV-bOPV-bOPV, 192 to IPV-IPV-bOPV, and 188 to IPV-IPV-IPV. 564 (99%) were vaccinated and included in the intention-to-treat cohort, and 537 (94%) in the per-protocol analyses. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroconversion to type 1 poliovirus were 166 (98·8%) of 168, 95% CI 95·8-99·7; 178 (100%), 97·9-100·0; and 175 (100%), 97·9-100·0. Proportions with seroconvsion to type 3 poliovirus were 163 (98·2%) of 166, 94·8-99·4; 177 (100%), 97·9-100·0, and 172 (98·9%) of 174, 95·9-99·7. Non-inferiority was thus shown for the bOPV-containing schedules compared with the all-IPV schedule, with no significant differences between groups. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroprotective antibody titres to type 1 poliovirus were 168 (98·8%) of 170, 95% CI 95·8-99·7; 181 (100%), 97·9-100·0; and 177 (100%), 97·9-100·0. Proportions to type 3 poliovirus were 166 (98·2%) of 169, 94·9-99·4; 180 (100%), 97·9-100·0; and 174 (98·9%) of 176, 96·0-99·7. Non-inferiority comparisons could not be done for this outcome because median titres for the groups receiving OPV were greater than the assay's upper limit of detection (log2 titres >10·5). The proportions of children seroconverting to type 2 poliovirus in the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, were 130 (77·4%) of 168, 95% CI 70·5-83·0; 169 (96·0%) of 176, 92·0-98·0; and 175 (100%), 97·8-100. IPV-bOPV schedules resulted in almost a 0·3 log reduction of type 2 faecal shedding compared with the IPV-only schedule. No participants died during the trial; 81 serious adverse events were reported, of which one was thought to be possibly vaccine-related (intestinal intussusception). INTERPRETATION: Seroconversion rates against polioviruses types 1 and 3 were non-inferior in sequential schedules containing IPV and bOPV, compared with an all-IPV schedule, and proportions of infants with protective antibodies were high after all three schedules. One or two doses of bOPV after IPV boosted intestinal immunity for poliovirus type 2, suggesting possible cross protection. Additionally, there was evidence of humoral priming for type 2 from one dose of IPV. Our findings could give policy makers flexibility when choosing a vaccination schedule, especially when trying to eliminate vaccine-associated and vaccine-derived poliomyelitis. FUNDING: Bill & Melinda Gates Foundation.

Desarrollo de una matriz conceptual para la innovación curricular en profesiones de la salud / Concept frame for curricular innovation in health care schools

We herein describe the conceptual dimension of the curricular innovation process carried out in the Faculty of Medicine of the University of Chile. We describe the context of innovation. The theoretical pertinence and relevance of a competence driven curriculum for health care professionals is discussed. The epistemological, ontological and didactic dimensions of the curricular innovation are examined. A main issue is the notion of competence and its significance in professional training. The curriculum is essentially considered as a moral endeavor, especially for health care professionals and their quest to improve the quality of life of the population.

A comparative study of two different methods for the detection of latent tuberculosis in HIV-positive individuals in Chile.

OBJECTIVE: To compare the performance of two tests for diagnosing latent tuberculosis (TB) infection in the HIV-positive population in Chile, in order to better identify the subjects who might benefit from TB chemoprophylaxis. DESIGN: This was a cross-sectional study among individuals attending three HIV outpatient clinics in Santiago, tested with a 2-TU purified protein derivative, QuantiFERON((R))-TB Gold 'in-tube' (QFT-G), and a chest X-ray. RESULTS: A total of 116 subjects were enrolled in the study, having a mean CD4 count of 393cells/microl (range 100-977). The tuberculin skin text (TST; 5mm cutoff) and QFT-G results were positive in 10.9% and 14.8% of the individuals, respectively, with moderate agreement between both tests (kappa=0.59). A history of both known TB exposure (odds ratio (OR) 3.46, 95% confidence interval (CI) 1.02-11.22) and past TB (OR 4.31, 95% CI 1.13-15.5) were associated with a positive QFT-G result. Only past TB was significantly associated with a positive TST result (OR 6.63, 95% CI 1.62-26.3). Among the subjects with TST<5mm, 8.2% were positive by QFT-G test. These individuals had a lower mean CD4 cell count than those detected positive by both tests (328cells/microl and 560cells/microl, respectively, p=0.03). CONCLUSIONS: In this population of HIV-infected individuals, QFT-G and TST showed an acceptable level of agreement, although QFT-G appears less affected by more advanced immunosuppression.