Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction.

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M-1 s-1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 107 M-1 s-1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

The influence of extrachromosomal elements in the anthrax "cross-over" strain Bacillus cereus G9241.

Bacillus cereus G9241 was isolated from a welder who survived a pulmonary anthrax-like disease. Strain G9241 carries two virulence plasmids, pBCX01 and pBC210, as well as an extrachromosomal prophage, pBFH_1. pBCX01 has 99.6% sequence identity to pXO1 carried by Bacillus anthracis and encodes the tripartite anthrax toxin genes and atxA, a mammalian virulence transcriptional regulator. This work looks at how the presence of pBCX01 and temperature may affect the lifestyle of B. cereus G9241 using a transcriptomic analysis and by studying spore formation, an important part of the B. anthracis lifecycle. Here we report that pBCX01 has a stronger effect on gene transcription at the mammalian infection relevant temperature of 37°C in comparison to 25°C. At 37°C, the presence of pBCX01 appears to have a negative effect on genes involved in cell metabolism, including biosynthesis of amino acids, whilst positively affecting the transcription of many transmembrane proteins. The study of spore formation showed B. cereus G9241 sporulated rapidly in comparison to the B. cereus sensu stricto type strain ATCC 14579, particularly at 37°C. The carriage of pBCX01 did not affect this phenotype suggesting that other genetic elements were driving rapid sporulation. An unexpected finding of this study was that pBFH_1 is highly expressed at 37°C in comparison to 25°C and pBFH_1 expression leads to the production of Siphoviridae-like phage particles in the supernatant of B. cereus G9241. This study provides an insight on how the extrachromosomal genetic elements in B. cereus G9241 has an influence in bacterial phenotypes.

Síndrome orbitofrontal en un interno con infracciones por secuestro agravado, violación sexual y muerte de una menor de edad

El síndrome orbitofrontal se caracteriza por la ausencia de inhibición, escaso control de impulsos, transgresión de normas sociales y, en determinados casos, con la materialización de conductas delictivas. Se presenta el caso de un interno varón de 18 años con infracciones por secuestro, violación sexual y homicidio de una menor de edad, a quien se evaluó a través de entrevistas y uso del test de Eysenck (Forma B), test de matrices progresivas de Raven, test de la figura compleja de Rey (Forma A), test de percepción de diferencias (Caras-R), test de Stroop (colores y palabras), test Mini-Mental y Cuestionario de cólera, irritabilidad y agresión (CIA). El evaluado muestra un lenguaje y vocabulario de acuerdo con su edad, no presenta problemas orgánicos, ni alteraciones en atención, lenguaje, escritura, lectura, praxias, cálculo, percepción y memoria. Los resultados destacan un coeficiente intelectual superior al término medio con óptimas capacidades cognitivas, temperamento melancólico con pensamientos depresivos, personalidad introvertida con baja sensibilidad a los cambios en el ambiente, escasa sociabilidad, ensimismamiento y evasión. Asimismo, evidencia tendencias perfeccionistas, con cambios emocionales bruscos y dificultad para reorientar patrones conductuales, alta tendencia a la impulsividad y escaso control inhibitorio; elementos característicos de un síndrome orbitofrontal. Finalmente, se destaca el uso de pruebas psicométricas y evaluaciones neuropsicológicas para el diagnóstico del síndrome orbitofrontal, necesarias a incorporar incorporar para el adecuado manejo de internos en los centros penitenciarios y/o de rehabilitación que no tienen acceso a estudios de neuroimagen y a partir de los cuales pueden diseñarse programas de intervención estratégicos.

Orbitofrontal syndrome is characterized by disinhibition, impulsiveness, transgression of social norms and sometimes the development of criminal behavior. This is the case of an 18-year-old male offender incarcerated for kidnapping, rape and homicide of a minor. He was evaluated through interviews and the use of the Eysenck personality questionnaire (Form B), Raven's progressive matrices (RPM), Rey-Osterrieth complex figure (Form A), Differences perception test (FACES-R), Stroop color and word test (SCWT), Mini-Mental state examination (MMSE) and Aggression questionnaire (AGQ). The research subject showed age-appropriate speech, language and vocabulary, and had neither physical problems nor attention, language, writing, reading, praxis, calculation, perception and memory disorders. The results highlight a higher-than-average intelligence quotient, optimal cognitive skills, melancholic temperament with depressive thoughts, introverted personality with low environmental sensitivity, poor social skills, self-absorption and avoidance. Additionally, perfectionist tendencies, sudden emotional changes, difficulty changing behavioral patterns, impulsiveness and disinhibition, all of which are characteristics of orbitofrontal syndrome. Finally, the research highlights the use of psychometric tests and neuropsychological evaluations for the diagnosis of orbitofrontal syndrome. Said tests and evaluations are necessary for the proper management of offenders incarcerated in prisons and/or detention centers who do not have access to neuroimaging; moreover, they may be used to design strategic intervention programs.

From cereus to anthrax and back again: Assessment of the temperature-dependent phenotypic switching in the "cross-over" strain Bacillus cereus G9241.

Bacillus cereus G9241 was isolated from a Louisiana welder suffering from an anthrax-like infection. The organism carries two transcriptional regulators that have previously been proposed to be incompatible with each other in Bacillus anthracis: the pleiotropic transcriptional regulator PlcR found in most members of the Bacillus cereus group but truncated in all B. anthracis isolates, and the anthrax toxin regulator AtxA found in all B. anthracis strains and a few B. cereus sensu stricto strains. Here we report cytotoxic and hemolytic activity of cell free B. cereus G9241 culture supernatants cultured at 25°C to various eukaryotic cells. However, this is not observed at the mammalian infection relevant temperature 37°C, behaving much like the supernatants generated by B. anthracis. Using a combination of genetic and proteomic approaches to understand this unique phenotype, we identified several PlcR-regulated toxins to be secreted highly at 25°C compared to 37°C. Furthermore, results suggest that differential expression of the protease involved in processing the PlcR quorum sensing activator molecule PapR appears to be the limiting step for the production of PlcR-regulated toxins at 37°C, giving rise to the temperature-dependent hemolytic and cytotoxic activity of the culture supernatants. This study provides an insight on how B. cereus G9241 is able to "switch" between B. cereus and B. anthracis-like phenotypes in a temperature-dependent manner, potentially accommodating the activities of both PlcR and AtxA.

Confirmation of the Y215H mutation in the ß2 -octopamine receptor in Varroa destructor is associated with contemporary cases of amitraz resistance in the United States.

BACKGROUND: The parasitic mite, Varroa destructor (Anderson and Trueman), is a leading cause of honey bee colony losses around the world. Application of miticides such as amitraz are often the primary method of Varroa control in commercial beekeeping operations in the United States. It is likely that excessive and exclusive amitraz application has led to the development of amitraz resistance in Varroa. A mutation of tyrosine at amino acid position 215 to histidine (Y215H) in the ß2 -octopamine receptor was identified in putatively amitraz-resistant Varroa in the United States. This research investigated the presence of the Y215H mutation in quantitatively confirmed amitraz-resistant Varroa from the United States. RESULTS: There was a strong association of susceptible and resistant phenotypes with the corresponding susceptible and resistant genotypes respectively, and vice versa. The resistance bioassay may understate resistance levels because of the influence of environmental conditions on the outcome of the test, whereby Varroa with an amitraz-resistant genotype may appear with a susceptible phenotype. CONCLUSION: Confirmation of the Y215H mutation in the ß2 -octopamine receptor of amitraz-resistant Varroa encourages the development and validation of low-cost, high-throughput genotyping protocols to assess amitraz resistance. Resistance monitoring via genotyping will allow for large-scale passive monitoring to accurately determine the prevalence of amitraz resistance rather than directed sampling of apiaries with known resistance issues. Genotyping of Varroa for amitraz resistance early in the beekeeping season may predict late-season resistance at the colony level and provide beekeepers with enough time to develop an effective Varroa management strategy. © 2023 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Improving emergency department care of infants with acute bronchiolitis by reducing the use of unrecommended drugs: a quality-of-care initiative in a Spanish autonomous community. / Iniciativa de mejora para reducir el uso de fármacos no recomendados en el manejo de lactantes con bronquiolitis aguda en los servicios de urgencias de una comunidad autónoma.

OBJECTIVES: To evaluate the impact of a quality-of-care improvement program implemented in emergency departments (EDs) in a Spanish autonomous community with the aim of reducing the use of unrecommended drugs when treating infants for acute bronchiolitis. MATERIAL AND METHODS: Before-after quasi-experimental intervention study. We retrospectively included infants aged 12 months or less who were treated for acute bronchiolitis in 24 Spanish national health system hospital EDs in December during 2 epidemic periods: in 2018, before implementing the program, and in 2019, after implementation. Data collected included epidemiologic information, clinical and care details, and clinical course. The program consisted of providing informative material and training sessions before the epidemic period started. RESULTS: A total of 7717 episodes (4007 in 2018 and 2710 in 2019) were identified. Epidemiologic and clinical characteristics did not differ between the 2 periods. ED use of the following treatments decreased between the 2 periods: salbutamol, from 29.4% (95% CI, 28.8%-30.8%) in 2018 to 10.6% (95% CI, 9.6%-11.6%) in 2019; epinephrine from 6.0% (95% CI, 5.3%-6.8%) to 0.9% (95% CI, 0.7%-1.3%); and hypertonic saline solution fell from 8.2% (95% CI, 7.3%-9.1%) to 2.1% (95% CI, 1.7%-2.6%) (P.001, all comparisons). Prescriptions for salbutamol on discharge fell from 38.7% (95% CI, 36.9%-40.4%) to 10.6% (95% CI, 9.6%-11.6%) (P.001). Admissions and readmissions did not change, and the median time (interquartile range) spent in the ED fell from 81 (44-138) minutes to 66 (37-127) minutes (P.001). CONCLUSION: The quality-of-care improvement initiative was able to decrease the number of unrecommended therapeutic interventions for acute bronchiolitis. However, we identified great variations between EDs, suggesting that training and assessment of impact should continue.

OBJETIVO: Evaluar el impacto de una iniciativa de mejora realizada en los servicios de urgencias (SU) de una comunidad autónoma para reducir el uso de fármacos no recomendados en lactantes con bronquiolitis aguda (BA). METODO: Estudio cuasi-experimental analítico del tipo "antes y después de una intervención". Se incluyeron de forma retrospectiva todas las BA en niños # 12 meses atendidas en los SU de 24 hospitales públicos durante el mes de diciembre de dos periodos epidémicos: 2018 (preintervención) y 2019 (postintervención). Se recogieron variables epidemiológicas, clínicas, asistenciales y evolutivas. La intervención consistió en difundir material informativo y realizar actividades formativas previas al periodo epidémico. RESULTADOS: Se incluyeron 7.717 episodios (2018: 4.007 y 2019: 3.710). No existieron diferencias en las características epidemiológicas y clínicas. El empleo de salbutamol en los SU descendió del 29,4% [intervalo de confianza del 95% (IC 95%): 28,8-30,8] en 2018 al 10,6% (IC 95%: 9,6-11,6) en 2019 (p 0,001), el de adrenalina del 6,0% (IC 95%: 5,3-6,8) al 0,9% (IC 95%: 0,7-1,3) y el de suero salino hipertónico del 8,2% (IC 95%: 7,3-9,1) al 2,1% (IC 95%: 1,7-2,6) (p 0,001). La prescripción al alta de salbutamol se redujo del 38,7% (IC 95%: 36,9-40,4) al 10,6% (IC 95%: 9,6-11,6) (p 0,001). La tasa de ingreso y la tasa de readmisión no cambiaron y la mediana de tiempo de estancia en los SU se redujo 81 minutos [rango intercuartil (RIC) 44-138] a 66 (RIQ: 37-127) (p 0,001). CONCLUSIONES: La iniciativa de mejora ha conseguido disminuir la tasa de intervenciones terapéuticas no indicadas en BA. Sin embargo, existe una gran variabilidad entre los diferentes SU por lo que la estrategia y la medición de su impacto deben mantenerse en el tiempo.

Frecuencia de migraña y discapacidad generada en estudiantes de medicina humana de una universidad privada en Lima, Perú / Frequency of migraine and disability generated in medical students at a private university in Lima Peru

Objetivo : Estimar la frecuencia de migraña, y discapacidad generada en estudiantes de medicina de una universidad privada de Lima Metropolitana. Métodos : Estudio transversal en una muestra no probabilística por conveniencia, mediante la aplicación online del autocuestionario ALCOI-95, para evaluar la presencia de migraña, seguido por el cuestionario MIDAS para medir la discapacidad en los positivos al primer cuestionario. El rendimiento académico fue evaluado mediante el promedio ponderado de sus calificaciones. Resultados : Cuarenticinco (21,6%) de 208 estudiantes experimentaron migraña (12,5% con aura y 9,1% sin aura), 14 (33,3%) de los cuales mostraron discapacidad severa y 12 (28,6%) moderada. Los portadores de migraña con aura tuvieron una media menor del promedio ponderado acumulado de sus calificaciones, comparado con aquellos con migraña sin aura. Los factores independientemente asociados a la migraña fueron tener un miembro de la familia nuclear con migraña y problemas para mantener el sueño. Conclusión : Dos de cada 10 estudiantes presentaron migraña y 1/3 de los afectados experimentó discapacidad severa.

SUMMARY Objective: To estimate the frequency of migraine, associated factors and disability generated (including its relationship with academic performance) in medical students at a private university in Metropolitan Lima. Methods: Cross-sectional study in a non-probabilistic convenience sample using the online application of the ALCOI-95 self-questionnaire, to assess the presence of migraine, followed by the MIDAS questionnaire to measure disability in those positive to the first questionnaire. . Results: Fourty-five (21.6%) of 208 students experienced migraine (12.5% with aura and 9.1% without aura), 14 (33.3%) of whom showed severe, and 12 (28.6%) moderate disability. Migraine with aura carriers had a lower mean than the cumulative weighted average of their academic scores. Independent factors associated with migraine were to have a nuclear family member with migraine, and sleep-maintenance problems. Conclusion: Two out of 10 students had migraine, and one third of them had severe disability.

Association between maternal depression and emotion and behavior regulation in Peruvian children: A population-based study.

Depression is more frequent in women, affecting the early stages of child development. This study aimed to determine the association between maternal depression and self-regulation of emotions and behaviors in Peruvian children under five years. A cross-sectional analytical study of data collected by the 2019 Demographic and Family Health Survey (ENDES) was conducted. The outcome variable was emotion and behavior regulation in children aged 24 to 59 months, and exposure was the presence of depression in women aged 15 to 49 years during the 14 days prior to the survey using the Patient Health Questionnaire (PHQ-9). A generalized linear model of the binomial family was used for reporting crude prevalence ratios and adjusted. The overall prevalence of children who did not self-regulate their emotions and behaviors was 68.8%, while 3.8% of the mothers had moderate depressive symptoms and 2.2% severe symptoms. Regarding the association of interest, moderate and severe depressive symptoms of mothers decreased the probability of children regulating emotions and behaviors in the first model, whereas in the second model, an association was only found with severe depressive symptoms. In conclusion, children of mothers with moderate and severe depressive symptoms had a lower probability of self-regulating their emotions and behaviors. Therefore, it is necessary to develop maternal education, nutritional and social support programs and mental health strategies from the first level of care aimed at reducing social, economic and child factors to reduce the risk of depression in mothers and low early childhood development, which could reduce the risk of developing mental health disorders in adolescence and adulthood.

Large-Scale Monitoring of Resistance to Coumaphos, Amitraz, and Pyrethroids in Varroa destructor.

Varroa destructor is an ectoparasitic mite causing devastating damages to honey bee colonies around the world. Its impact is considered a major factor contributing to the significant seasonal losses of colonies recorded every year. Beekeepers usually rely on a reduced set of acaricides to manage the parasite, usually the pyrethroids tau-fluvalinate or flumethrin, the organophosphate coumaphos, and the formamidine amitraz. However, the evolution of resistance in the mite populations is leading to an unsustainable scenario with almost no alternatives to reach an adequate control of the mite. Here, we present the results from the first large-scale and extensive monitoring of the susceptibility to acaricides in the Comunitat Valenciana, one of the most prominent apicultural regions in Spain. Our ultimate goal is to provide beekeepers with timely information to help them decide what would be the best alternative for a long-term control of the mites in their apiaries. Our data show that there is a significant variation in the expected efficacy of coumaphos and pyrethroids across the region, indicating the presence of a different ratio of resistant individuals to these acaricides in each population. On the other hand, the expected efficacy of amitraz was more consistent, though slightly below the expected efficacy according to the label.

Assessing the resistance to acaricides in Varroa destructor from several Spanish locations.

Varroosis is the disease caused by the ectoparasitic mite Varroa destructor, one of the most destructive diseases of honeybees. In Spain, there is great concern because there are many therapeutic failures after acaricide treatments intended to control varroosis outbreaks. In some of these cases it is not clear whether such failures are due to the evolution of resistance. Therefore, it is of high interest the development of methodologies to test the level of resistance in mite populations. In this work, a simple bioassay methodology was used to test whether some reports on low efficacy in different regions of Spain were in fact related to reduced Varroa sensitivity to the most used acaricides. This bioassay proved to be very effective in evaluating the presence of mites that survive after being exposed to acaricides. In the samples tested, the mortality caused by coumaphos ranged from 2 to 89%; for tau-fluvalinate, it ranged from 5 to 96%. On the other hand, amitraz caused 100% mortality in all cases. These results suggest the presence of Varroa resistant to coumaphos and fluvalinate in most of the apiaries sampled, even in those where these active ingredients were not used in the last years. The bioassay technique presented here, either alone or in combination with other molecular tools, could be useful in detecting mite populations with different sensitivity to acaricides, which is of vital interest in selecting the best management and/or acaricide strategy to control the parasite in apiaries.

[Guidelines and strategies to improve the quality of care in health services]. / Lineamientos y estrategias para mejorar la calidad de la atención en los servicios de salud.

The challenge of Universal Health Coverage (UHC) led countries to make greater efforts to increase the proportion of population protected, to define and expand their benefit plans, and to provide financial resources to support payment for the benefits provided. The implementation of the health insurance policy in our country has allowed reaching important milestones, evidencing, however, an insufficient effect on timely access and on meeting the health needs of a large portion of the population. In this article we begin by highlighting the main advances and limitations in the process towards a UHC, guding the development of the pending agenda, based on the proposals issued by international organizations aimed at improving health systems globally. The pending challenges include efforts to involve and articulate the various actors in the task at hand of redesigning healthcare processes, strengthening the ethical dimension of their practice, as well as promoting citizen participation in the generation of a high-quality health system that would facilitate effective and timely access to health services. This requires the adoption of measures that extend to the entire health system, based on a shared vision and led by those responsible for its execution and governance.

El desafío de la Cobertura Universal en Salud (CUS) orientó a los países a desplegar sus mayores esfuerzos en la ampliación de la proporción de población protegida, la delimitación y ampliación de sus planes de beneficios, así como en la provisión de recursos financieros que permitan respaldar el pago de las prestaciones brindadas. En nuestro país, a través de la implementación de la política de aseguramiento en salud, ha sido posible arribar a importantes logros, evidenciando, sin embargo, un insuficiente efecto en el acceso oportuno y en la satisfacción de las necesidades de salud de gran parte de la población. En el presente artículo partimos por destacar los principales avances y limitaciones en el proceso hacia una CUS, orientando el desarrollo de la agenda pendiente, sobre la base de los planteamientos emitidos por Organizaciones Internacionales que apuntan hacia una mejora de los sistemas de salud a nivel global. Los desafíos pendientes incluyen esfuerzos de involucramiento y articulación de los diversos actores, en la tarea de rediseñar los procesos de atención, fortalecer la dimensión ética de su ejercicio, así como promover la participación ciudadana en la generación de un sistema de salud de alta calidad, que permita un acceso efectivo y oportuno a servicios de salud; ello obliga a adoptar medidas que alcancen a todo el sistema de salud, orientadas en una visión compartida y liderada por los responsables de su conducción y gobierno.

Lineamientos y estrategias para mejorar la calidad de la atención en los servicios de salud / Guidelines and strategies to improve the quality of care in health services

RESUMEN El desafío de la Cobertura Universal en Salud (CUS) orientó a los países a desplegar sus mayores esfuerzos en la ampliación de la proporción de población protegida, la delimitación y ampliación de sus planes de beneficios, así como en la provisión de recursos financieros que permitan respaldar el pago de las prestaciones brindadas. En nuestro país, a través de la implementación de la política de aseguramiento en salud, ha sido posible arribar a importantes logros, evidenciando, sin embargo, un insuficiente efecto en el acceso oportuno y en la satisfacción de las necesidades de salud de gran parte de la población. En el presente artículo partimos por destacar los principales avances y limitaciones en el proceso hacia una CUS, orientando el desarrollo de la agenda pendiente, sobre la base de los planteamientos emitidos por Organizaciones Internacionales que apuntan hacia una mejora de los sistemas de salud a nivel global. Los desafíos pendientes incluyen esfuerzos de involucramiento y articulación de los diversos actores, en la tarea de rediseñar los procesos de atención, fortalecer la dimensión ética de su ejercicio, así como promover la participación ciudadana en la generación de un sistema de salud de alta calidad, que permita un acceso efectivo y oportuno a servicios de salud; ello obliga a adoptar medidas que alcancen a todo el sistema de salud, orientadas en una visión compartida y liderada por los responsables de su conducción y gobierno.

ABSTRACT The challenge of Universal Health Coverage (UHC) led countries to make greater efforts to increase the proportion of population protected, to define and expand their benefit plans, and to provide financial resources to support payment for the benefits provided. The implementation of the health insurance policy in our country has allowed reaching important milestones, evidencing, however, an insufficient effect on timely access and on meeting the health needs of a large portion of the population. In this article we begin by highlighting the main advances and limitations in the process towards a UHC, guding the development of the pending agenda, based on the proposals issued by international organizations aimed at improving health systems globally. The pending challenges include efforts to involve and articulate the various actors in the task at hand of redesigning healthcare processes, strengthening the ethical dimension of their practice, as well as promoting citizen participation in the generation of a high-quality health system that would facilitate effective and timely access to health services. This requires the adoption of measures that extend to the entire health system, based on a shared vision and led by those responsible for its execution and governance.

[The medical major of health management in Universidad Nacional Mayor de San Marcos: 30 years training managers for the health sector]. / La especialidad medica de gestión en salud en la Universidad Nacional Mayor de San Marcos: 30 años formando gestores para el sector salud.

A historical account of the 30 years of the medical major of Health Management at Universidad Nacional Mayor de San Marcos is presented. The major was created in 1988 as Comprehensive General Medicine in response to the shortage of management specialists. The name of the major remained until 1994, when it changed to Integral Medicine and Health Management to emphasize its managerial orientation. In 2002, the curricular plan was modified considering the importance of having an exclusive medical specialization in management for the health sector. The specialty is a pioneer in a gradual education in three levels: micro-management, meso-management, and macro-management. The new curricular plan allowed residents the possibility to access better rotations at public and private institutions. Since 2007, the major is labeled Health Management, and its specialists maintain their solid training that enables them to perform in the decision-making, management, administration, and operation processes of the health systems. The vision of the creators of this major is current to this day; Health Management specialists work in the different institutions of the health system, contributing their knowledge and skills, and generating an impact on the health of the Peruvian population.

Se presenta un recuento histórico de los 30 años de la especialidad médica de Gestión en Salud en la Universidad Nacional Mayor de San Marcos. La especialidad fue creada en 1988 como Medicina General Integral en respuesta a la escasez de médicos especialistas en gestión. El nombre de la especialidad se mantuvo hasta 1994, cuando cambia a Medicina Integral y Gestión en Salud para enfatizar su orientación gerencial. En 2002, se modifica el plan curricular considerando la importancia de tener una especialización médica exclusiva de gestión para el sector salud. La especialidad es pionera en una formación gradual en tres niveles: microgestión, mesogestión y macrogestión. El nuevo plan curricular permitió a los residentes la posibilidad de mejores rotaciones en instituciones públicas y privadas. A partir del 2007, la especialidad es denominada Gestión en Salud, cuyos médicos especialistas mantienen su sólida formación para desempeñarse en los procesos de decisión, conducción, dirección y operatividad de los sistemas de salud. La visión de los creadores de la especialidad se encuentra vigente, los especialistas de Gestión en Salud se desempeñan en las diferentes instituciones del sistema de salud, aportando sus conocimientos y habilidades, y generando un impacto en la salud de la población peruana.

La especialidad médica de gestión en salud en la Universidad Nacional Mayor de San Marcos: 30 años formando gestores para el sector salud / The medical major of health management in Universidad Nacional Mayor de San Marcos: 30 years training managers for the health sector

Se presenta un recuento histórico de los 30 años de la especialidad médica de Gestión en Salud en la Universidad Nacional Mayor de San Marcos. La especialidad fue creada en 1988 como Medicina General Integral en respuesta a la escasez de médicos especialistas en gestión. El nombre de la especialidad se mantuvo hasta 1994, cuando cambia a Medicina Integral y Gestión en Salud para enfatizar su orientación gerencial. En 2002, se modifica el plan curricular considerando la importancia de tener una especialización médica exclusiva de gestión para el sector salud. La especialidad es pionera en una formación gradual en tres niveles: microgestión, mesogestión y macrogestión. El nuevo plan curricular permitió a los residentes la posibilidad de mejores rotaciones en instituciones públicas y privadas. A partir del 2007, la especialidad es denominada Gestión en Salud, cuyos médicos especialistas mantienen su sólida formación para desempeñarse en los procesos de decisión, conducción, dirección y operatividad de los sistemas de salud. La visión de los creadores de la especialidad se encuentra vigente, los especialistas de Gestión en Salud se desempeñan en las diferentes instituciones del sistema de salud, aportando sus conocimientos y habilidades, y generando un impacto en la salud de la población peruana.

A historical account of the 30 years of the medical major of Health Management at Universidad Nacional Mayor de San Marcos is presented. The major was created in 1988 as Comprehensive General Medicine in response to the shortage of management specialists. The name of the major remained until 1994, when it changed to Integral Medicine and Health Management to emphasize its managerial orientation. In 2002, the curricular plan was modified considering the importance of having an exclusive medical specialization in management for the health sector. The specialty is a pioneer in a gradual education in three levels: micro-management, meso-management, and macro-management. The new curricular plan allowed residents the possibility to access better rotations at public and private institutions. Since 2007, the major is labeled Health Management, and its specialists maintain their solid training that enables them to perform in the decision-making, management, administration, and operation processes of the health systems. The vision of the creators of this major is current to this day; Health Management specialists work in the different institutions of the health system, contributing their knowledge and skills, and generating an impact on the health of the Peruvian population.

Genetic variability and pyrethroid susceptibility of the parasitic honey bee mite Varroa destructor (Acari: Varroidae) in Iran.

The ectoparasitic honey bee mite Varroa destructor Anderson & Trueman (Acari: Varroidae) is one of the major concerns for worldwide beekeeping. The use of synthetic pyrethroids for controlling the mite was among the most popular treatments until resistance evolved in the mid 1990's. In Iran, beekeepers are dealing with the parasite and they also used pyrethroids for controlling the mite for a long time. After the evolution of resistance to pyrethroids, they based mite control mostly on treatments with amitraz, organic acids and several management practices. Here we conducted a comprehensive characterization of V. destructor populations parasitizing Apis mellifera in Iran. We determined the genetic variability of mites collected from 28 localities distributed throughout the country. The haplotype of V. destructor was determined by PCR-RFLP, analyzing a fragment of the mitochondrial cox1 gene. It was found that only the Korean haplotype was present in samples from all localities. DNA fragments from cox1, atp6, cox3 and cytb mitochondrial genes were sequenced and the results showed that all samples were identical to the K1-1 or the K1-2 V. destructor haplotypes. Moreover, as it has been reported that resistance to pyrethroids in V. destructor is associated with mutations at position 925 of the voltage-gated sodium channel, a TaqMan®-based allelic discrimination assay was conducted to genotype the mites collected. The results showed that all the mites tested were homozygous for the wild-type allele and, therefore, susceptible to treatment with pyrethroids.

Brecha entre cobertura poblacional y prestacional en salud: un reto para la reforma de salud en el Perú / Gap between population coverage and health benefits: A challenge for health reform in Peru

El Aseguramiento Universal en Salud constituye una de las principales políticas públicas impulsadas en la última década en nuestro país, y se ha mantenido por más de cuatro administraciones nacionales en la agenda política. Los avances en este proceso pueden verse reflejados en el incremento en la cobertura de afiliación a algún tipo de seguro de salud, que para el caso del Seguro Integral de Salud (SIS), fue ampliada de 19,4% en el año 2006 a 50,2% para el año 2015 (Encuesta Nacional de Hogares - ENAHO). Sin embargo, es posible evidenciar que mientras en el 2006 el 44,9% de los afiliados al SIS buscaban atención por problemas de salud en establecimientos del MINSA o de las redes de salud públicas de los Gobiernos Regionales, en el año 2015 este porcentaje disminuyó a 31,7%. Estos resultados obligan a prestar atención a otros factores que estarían restringiendo la mejora en el acceso a los servicios de salud, especialmente en pobladores pobres protegidos financieramente. Entre los retos para incrementar la cobertura prestacional se encuentran la brecha de infraestructura y equipamiento de servicios de salud, la poca articulación de los establecimientos de salud del primer nivel de atención, la subutilización de la oferta pública existente y recurso humano no bien remunerado con escasos o nulos incentivos.

Health Universal Coverage is one of the principal public policy impulsed in the last decade in our country, despite four different national administrations their importance remains in the agenda. The advances in this process are evident in the increment of the insurance coverage, that in case of Seguro Integral de Salud (SIS) was broaded from 19,4% in 2006 to 50,2% in 2015 (National Household Survey - NHS). However, it is real that while in 2006, 44,9% of affiliates to SIS sought attention for health problems in public health establishments of national, regional o local level, this proportion decrease to 31,7% in 2015. These results force us to pay attention to other factors that would be restricting the improvement in the health services access, especially in poor people protected financially. Among the challenges to increase the provisional coverage are the gap in infrastructure and health services equipment, the poor articulation of health care facilities at the primary care, the underuse of the existing public offering and poorly remunerated human resources with little or no incentives.

Engineering the expression of an anti-interleukin-13 antibody through rational design and mutagenesis.

High levels of protein expression are key to the successful development and manufacture of a therapeutic antibody. Here, we describe two related antibodies, Ab001 and Ab008, where Ab001 shows a markedly lower level of expression relative to Ab008 when stably expressed in Chinese hamster ovary cells. We use single-gene expression vectors and structural analysis to show that the reduced titer is associated with the VL CDR2 of Ab001. We adopted two approaches to improve the expression of Ab001. First, we used mutagenesis to change single amino-acid residues in the Ab001 VL back to the equivalent Ab008 residues but this resulted in limited improvements in expression. In contrast when we used an in silico structure-based design approach to generate a set of five individual single-point variants in a discrete region of the VL, all exhibited significantly improved expression relative to Ab001. The most successful of these, D53N, exhibited a 25-fold increase in stable transfectants relative to Ab001. The functional potency of these VL-modified antibodies was unaffected. We expect that this in silico engineering strategy can be used to improve the expression of other antibodies and proteins.

Insecticidal spectrum and mode of action of the Bacillus thuringiensis Vip3Ca insecticidal protein.

The Vip3Ca protein, discovered in a screening of Spanish collections of Bacillus thuringiensis, was known to be toxic to Chrysodeixis chalcites, Mamestra brassicae and Trichoplusia ni. In the present study, its activity has been tested with additional insect species and we found that Cydia pomonella is moderately susceptible to this protein. Vip3Ca (of approximately 90kDa) was processed to an approximately 70kDa protein when incubated with midgut juice in all tested species. The kinetics of proteolysis correlated with the susceptibility of the insect species to Vip3Ca. The activation was faster to slower in the following order: M. brassicae (susceptible), Spodoptera littoralis (moderately susceptible), Agrotis ipsilon and Ostrinia nubilalis (slightly susceptible). Processing Vip3Ca by O. nubilalis or M. brassicae midgut juice did not significantly changed its toxicity to either insect species, indicating that the low susceptibility of O. nubilalis is not due to a problem in the midgut processing of the toxin. M. brassicae larvae fed with Vip3Ca showed binding of this toxin to the apical membrane of the midgut epithelial cells. Histopathological inspection showed sloughing of the epithelial cells with further disruption, which suggests that the mode of action of Vip3Ca is similar to that described for Vip3Aa. Biotin-labeled Vip3Ca and Vip3Aa bound specifically to M. brassicae brush border membrane vesicles and both toxins competed for binding sites. This result suggests that insects resistant to Vip3A may also be cross-resistant to Vip3C, which has implications for Insect Resistance Management (IRM).

Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation.

In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site. Both reduced (active) and disulphide bonded (inactive) forms of IL-33 can be detected in lung lavage samples from mice challenged with Alternaria extract and in sputum from patients with moderate-severe asthma. We propose that this mechanism for the rapid inactivation of secreted IL-33 constitutes a 'molecular clock' that limits the range and duration of ST2-dependent immunological responses to airway stimuli. Other IL-1 family members are also susceptible to cysteine oxidation changes that could regulate their activity and systemic exposure through a similar mechanism.