Assessing and mitigating pH-mediated DDI risks in drug development - formulation approaches and clinical considerations.

pH-mediated drug-drug interactions (DDI) is a prevalent DDI in drug development, especially for weak base compounds with highly pH-dependent solubility. FDA has released a guidance on the evaluation of pH-mediated DDI assessments using in vitro testing and clinical studies. Currently, there is no common practice of ways of testing across the academia and industry. The development of biopredictive method and physiologically-based biopharmaceutics modeling (PBBM) approaches to assess acid-reducing agent (ARA)-DDI have been proven with accurate prediction and could decrease drug development burden, inform clinical design and potentially waive clinical studies. Formulation strategies and careful clinical design could help mitigate the pH-mediated DDI to avoid more clinical studies and label restrictions, ultimately benefiting the patient. In this review paper, a detailed introduction on biorelevant dissolution testing, preclinical and clinical study requirement and PBPK modeling approaches to assess ARA-DDI are described. An improved decision tree for pH-mediated DDI is proposed. Potential mitigations including clinical or formulation strategies are discussed.

DNA oxidative damage in oral cancer: 8-hydroxy-2´-deoxyguanosine immunoexpression assessment.

BACKGROUND: The development and establishment of oral squamous cell carcinoma are confined to carcinogenesis, which involves oxidative stress via oxygen-free radical production as a hydroxyl radical (HO•), considered the most important cause of oxidative damage to basic biomolecules since it targets DNA strands. 8-Hydroxy-2´-deoxyguanosine (8-OHdG) is considered a free radical with a promutagenic capacity due to its ability to pair with adenosine instead of cytosine during replication. MATERIAL AND METHODS: We collected 30 paraffin-embedded tissue samples of OSCC from patients treated between 2013 and 2018. We recorded risk habits, disease stage, disease free survival and death with at least 3 years of follow-up. 8-Hydroxyguanosine was evaluated by immunohistochemistry and subsequently classified as weak-moderate or strong positive expression. Additionally, we noted whether it was expressed in the cytoplasm and/or nucleus. RESULTS: Most of the cases expressed 8-OHdG with a strong intensity (80%). All neoplastic cells were preferentially stained in only the cytoplasm (70.0%), but nuclear positivity was found in 30%, independent of the intensity. Based on the location in the cytoplasm and/or nucleus, tumors >4 cm showed a high frequency (95.5%) of 8-OHdG expression in only the cytoplasm, with a significant difference (p value 0.001). Additionally, overall survival was affected when immunoexpression was present in the cytoplasm and nucleus because all deaths were in this group were statistically significant (p value = 0.001). CONCLUSIONS: All tumors showed DNA oxidative damage, and 8-OHdG was preferentially expressed in the cytoplasm. This finding was associated with tumor size and, when present in the nucleus, might also be related to death.

Hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: experience in a pediatric oncological institution. / Cistitis hemorrágica tras trasplante alogénico de progenitores hematopoyéticos: experiencia en un centro oncológico pediátrico.

OBJECTIVE: To analyze the risk factors associated with hemorrhagic cystitis (HC) severity and the treatment strategies available in HC patients following allogeneic hematopoietic stem cell transplantation (AHSCT). MATERIALS AND METHODS: A retrospective study of medical records was carried out. Patients with HC following AHSCT treated from 2017 to 2021 were divided into two groups according to severity -mild and severe. Demographic data, disease-specific characteristics, urological sequelae, and overall mortality were compared between both groups. The hospital's protocol was used for patient management. RESULTS: 33 episodes of HC were collected in 27 patients, 72.7% of whom were male. HC incidence following AHSCT was 23.4% (33/141). 51.5% of HCs were severe (grades III-IV). Severe graft host disease (GHD) (grades III-IV) and thrombopenia at HC onset were associated with severe HC (p= 0.043 and p= 0.039, respectively). This group had longer hematuria times (p< 0.001) and required more platelet transfusions (p= 0.003). In addition, 70.6% required bladder catheterization, but only 1 case needed percutaneous cystostomy. None of the patients with mild HC required catheterization. No differences were found in terms of urological sequelae or overall mortality. CONCLUSIONS: Severe HC could be predicted thanks to the presence of severe GHD or thrombopenia at HC onset. Severe HC can be managed with bladder catheterization in most of these patients. A standardized protocol may help reduce the need for invasive procedures in patients with mild HC.

OBJETIVO: Analizar factores de riesgo asociados a la gravedad de la cistitis hemorrágica (CH) y estrategias de tratamiento en pacientes con CH tras trasplante alogénico de progenitores hematopoyéticos (TAPH). MATERIAL Y METODOS: Estudio retrospectivo de historias clínicas. Los pacientes con CH tras TAPH tratados entre 2017 y 2021 se dividieron en dos grupos según la gravedad del cuadro (leve y grave). Se compararon datos demográficos, características específicas de la enfermedad, secuelas urológicas y mortalidad global entre ambos grupos. Se utilizó el protocolo del hospital para el manejo de los pacientes. RESULTADOS: Se recogieron 33 episodios de CH en 27 pacientes, de los cuales el 72,7% fueron varones. La incidencia de CH tras TAPH fue del 23,4% (33/141). El 51,5% de las CH fueron graves (grados III-IV). La enfermedad de injerto contra huésped (EICH) grave (grados III-IV) y la trombopenia al inicio se asociaron a CH grave (p= 0,043 y p= 0,039, respectivamente). Este grupo tuvo mayor tiempo de hematuria (p< 0,001) y necesitó más transfusiones de plaquetas (p= 0,003). Además, el 70,6% precisó sondaje vesical, pero solo un caso cistostomía percutánea. Ningún paciente con CH leve precisó sondaje. No hubo diferencias en las secuelas urológicas ni en la mortalidad global. CONCLUSIONES: Una CH más grave podría predecirse por la presencia de EICH grave o trombopenia al inicio del cuadro. La CH grave puede manejarse con sondaje vesical en la mayoría de estos pacientes. Seguir un protocolo estandarizado puede reducir la necesidad de procedimientos invasivos en pacientes con CH leve.

Cistitis hemorrágica tras trasplante alogénico de progenitores hematopoyéticos: experiencia en un centro oncológico pediátrico / Hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: experience in a pediatric oncological institution

Objetivos: Analizar factores de riesgo asociados a la gravedad de lacistitis hemorrágica (CH) y estrategias de tratamiento en pacientes conCH tras trasplante alogénico de progenitores hematopoyéticos (TAPH).Material y métodos: Estudio retrospectivo de historias clínicas. Lospacientes con CH tras TAPH tratados entre 2017 y 2021 se dividieronen dos grupos según la gravedad del cuadro (leve y grave). Se compararon datos demográficos, características específicas de la enfermedad,secuelas urológicas y mortalidad global entre ambos grupos. Se utilizóel protocolo del hospital para el manejo de los pacientes. Resultados: Se recogieron 33 episodios de CH en 27 pacientes, delos cuales el 72,7% fueron varones. La incidencia de CH tras TAPH fuedel 23,4% (33/141). El 51,5% de las CH fueron graves (grados III-IV).La enfermedad de injerto contra huésped (EICH) grave (grados III-IV) yla trombopenia al inicio se asociaron a CH grave (p= 0,043 y p= 0,039,respectivamente). Este grupo tuvo mayor tiempo de hematuria (p<0,001)y necesitó más transfusiones de plaquetas (p= 0,003). Además, el 70,6%precisó sondaje vesical, pero solo un caso cistostomía percutánea. Ningún paciente con CH leve precisó sondaje. No hubo diferencias en lassecuelas urológicas ni en la mortalidad global. Conclusiones: Una CH más grave podría predecirse por la presenciade EICH grave o trombopenia al inicio del cuadro. La CH grave puedemanejarse con sondaje vesical en la mayoría de estos pacientes. Seguirun protocolo estandarizado puede reducir la necesidad de procedimientosinvasivos en pacientes con CH leve.(AU)

Objective: To analyze the risk factors associated with hemorrhagiccystitis (HC) severity and the treatment strategies available in HC patientsfollowing allogeneic hematopoietic stem cell transplantation (AHSCT). Materials and methods: A retrospective study of medical recordswas carried out. Patients with HC following AHSCT treated from 2017to 2021 were divided into two groups according to severity –mild andsevere. Demographic data, disease-specific characteristics, urologicalsequelae, and overall mortality were compared between both groups.The hospital’s protocol was used for patient management. Results: 33 episodes of HC were collected in 27 patients, 72.7% ofwhom were male. HC incidence following AHSCT was 23.4% (33/141).51.5% of HCs were severe (grades III-IV). Severe graft host disease(GHD) (grades III-IV) and thrombopenia at HC onset were associatedwith severe HC (p= 0.043 and p= 0.039, respectively). This group hadlonger hematuria times (p< 0.001) and required more platelet transfusions (p= 0.003). In addition, 70.6% required bladder catheterization,but only 1 case needed percutaneous cystostomy. None of the patientswith mild HC required catheterization. No differences were found interms of urological sequelae or overall mortality. Conclusions: Severe HC could be predicted thanks to the presenceof severe GHD or thrombopenia at HC onset. Severe HC can be managedwith bladder catheterization in most of these patients. A standardizedprotocol may help reduce the need for invasive procedures in patientswith mild HC.(AU)

Vascular characterization and morphogenesis in porcine placenta at day 40 of gestation.

In porcine placenta, abnormal development of the placental vasculature leads to placental insufficiency. The aim of this study was to determine the mRNA expression of angiogenic growth factors and to determine the vascular characteristics in placenta at day 40 of pig gestation. Samples were collected from maternal-chorioallantoic interface (n = 21) for the measurement of mRNA expression of VEGFA, ANGPT1, ANGPT2, FGF2 and its receptors KDR, TEK, FGFR1IIIc, FGFR2IIIb respectively, and for immunohistochemistry analysis of CD31 and VEGFA. Immunohistochemical analysis of CD31 and VEGFA, morphometric measurement of blood vessels, high-resolution light microscopy and transmission electron microscopy were performed. Capillary area density, number of blood vessels and capillary area were significantly higher on the maternal side than on the fetal side (p < .05). The ultrastructural finding of blood vessels demonstrates close contact with the trophoblastic epithelium. The relative mRNA expression of VEGFA and its receptor KDR was higher compared with the other angiogenic genes. In conclusion, a high mRNA expression of VEGFA and its receptor KDR added to the immunohistochemical results suggest a potential role of these genes in this pathway associated with an increase in the density of the capillary area on the maternal side and a reduction in the hemotrophic diffusion distance at the interface for nutrient exchange.

Descripción de las tasas de egresos hospitalarios por psoriasis entre los años 2018 a 2021 en Chile / Psoriasis hospital discharge rates description from 2018 to 2021 in Chile

Introducción: La psoriasis es una enfermedad crónica con diversas manifestaciones cutáneas que presenta asociación con patologías cardiovasculares y reumatológicas y que puede requerir manejo hospitalizado. El objetivo de este estudio fue describir la tasa de egresos hospitalarios por psoriasis entre los años 2018-2021 en Chile. Metodología: Estudio descriptivo observacional, sobre egresos hospitalarios por psoriasis entre 2018-2021, Chile, según sexo y grupos etario (n=2463). Datos obtenidos del Departamento de estadística e información de Salud. Se calculó la Tasa de egreso hospitalario (TEH). No se requirió comité de ética. Resultados: El año 2020 y 2021 se presentó la menor TEH del periodo de estudio con 2.8 y 2.09/100.000 hab respectivamente. El sexo masculino presento la mayor TEH del periodo con 4.96, y el grupo etario de 45-64 años presento la mayor TEH con 6.97/100000 habitantes. Discusión: En el año 2020 y 2021 se evidenció una reducción de la tasa de egreso hospitalario, que coincide con la declaración de pandemia en el año 2020 producto del virus SARS-CoV-2 y esto puede deberse a una reconversión de camas, a camas respiratorias. El sexo femenino podría presentar menor TEH debido a que el estrógeno se reporta como un factor protector. La mayor TEH en el grupo etario 45-64 puede explicarse debido a que esta población presenta más comorbilidades que predisponen a la psoriasis. Conclusión: Se requieren más estudios a nivel nacional para profundizar en los resultados encontrados. Existe escasez de estadísticas nacionales de tasa de egreso de psoriasis siendo interesante aumentar el periodo de tiempo estudiado para profundizar los hallazgos reportados.

Introduction: Psoriasis is a chronic disease with a diversity of skin manifestations, whose etiology is multifactorial and associated with cardiovascular and rheumatological pathologies and that may require hospitalization. The objective of this study was to describe the rate of hospital discharges due to psoriasis between the years 2018-2021 in Chile. Methodology: Observational descriptive study on hospital discharges for psoriasis between 2018-2021 in Chile according to sex and age groups (n=2463).. The data was obtained from the Department of Statistics and Health Information (DEIS). The Hospital Discharge Rate (TEH) was calculated. No ethics committee was required. Results: The year 2020 and 2021 presented the lowest TEH of the study period with 2.8 and 2.09/100,000 habitants respectively. The male sex presented the highest TEH of the period with 4.96, and the age group of 45-64 years presented the highest TEH with 6.97/100,000 habitants. Discussion: In 2020 and 2021, there was a reduction in the hospital discharge rate, which coincides with the declaration of a pandemic in 2020 as a result of the SARS-CoV-2 virus and this may be due to a conversion of beds to respiratory beds. The female sex could present lower TEH because estrogen is reported as a protective factor. The higher TEH in the 45-64 age group can be explained by the fact that this population presents more comorbidities that predispose to psoriasis. Conclusion: More studies are required at a national level to deepen the results found. There is a scarcity of national statistics on the rate of discharge from psoriasis, and it is interesting to increase the period of time studied to deepen the reported findings.

Descripción de las tasas de mortalidad por cáncer gástrico como causa básica entre los años 2017 a 2021 en Chile / Description of death rates due to gastric cancer as a basic cause between 2017 and 2021 in Chile

Introducción: El cáncer gástrico, en Chile, ocupa el primer lugar como causa de mortalidad por tumores malignos, por ello, es de suma importancia conocer la descripción demográfica de esta enfermedad en el país. El periodo en estudio 2017-2021 entrega información actualizada a la salud pública. Metodología: Estudio ecológico, observacional, transversal y descriptivo sobre defunciones por cáncer gástrico en el periodo 2017-2021 en Chile según sexo, grupo etario y regiones (n=15350). Se calculó la tasa de mortalidad (TM). Información obtenida del Departamento de Estadística e Información de Salud e Instituto Nacional de Estadísticas, por lo que no requiere comité de ética. Resultados: Durante el periodo 2017-2021 la TM general fue de 21,84, siendo 21,58 en hombres y 10,68 en mujeres. En edad, el mayor valor se presentó en el grupo de 80 y más años y el menor valor en el grupo de 15-19 años. La TM del periodo general más alta la obtuvo la Región Metropolitana. Discusión: Se evidenció una reducción de la TM entre los años 2017-2021, pudiéndose deber al aumento de tamizaje y tratamiento de Helicobacter pylori. Además, se observó que la TM es mayor en hombres, explicado por su mayor susceptibilidad genética a desarrollar cáncer. La menor TM se registró entre 15-19 años, y la mayor en el grupo 80 y más años, lo que concuerda con literatura internacional. Conclusión: Se necesitan más estudios nacionales para ahondar en los resultados encontrados que permitan darle continuidad a la investigación, y que determinen factores de riesgo específicos de la población chilena.

Introduction: Gastric cancer in Chile takes the first place as a cause of mortality from malignant tumors, therefore it is relevant to know the demographic description of this disease in the country. Studied years go from 2017-2021 in order to get updated data to the Chilean public health. Methodology: Ecological, observational, cross-sectional and descriptive study on deaths due to gastric cancer in 2017-2021 in Chile, according to sex, age group and regions (n=15350). The death rate was calculated. Data was obtained from the Department of Statistics and Health Information and the National Institute of Statistics. It did not require approval from an ethics committee. Results: During the 2017-2021 period the overall death rate was 21.84, 21,58 for men and 10,68 for women. The highest values were in the 80 and older age group and the lowest values in the 15-19 years age group. The highest death rate overall period was registered in the Metropolitan Region. Discussion: There was a reduction in the hospital death rate between 2017-2021, which could be due to the increase in screening and treatment of Helicobacter pylori. Death rate is higher in men, which could be explained because they are more genetically susceptible to developing cancer. The lowest values for death rate were found in the 15-19 years age group, and the highest values in the 80 years and older group, which is consistent with international literature. Conclusion: More studies are required in Chile to broaden the findings to allow investigation continuity and to determine specific risk factors present in the Chilean population.

Ep-CAM (MOC-31) expression in tooth germ and ameloblastoma.

BACKGROUND: Ep-CAM, a transmembrane glycoprotein expressed in most epithelium in normal conditions, has diverse roles in these tissues, including in cell adhesion, proliferation, differentiation, cell cycle regulation, migration and intracellular signaling. It is also over-expressed in most malignant neoplasia, participating in the initiation, progression, and metastatic dissemination of the tumor. The expression and roles of this protein in oral neoplasia, particularly in odontogenic tumors, remain unestablished. The objective of this study consisted in analyzing the expression of this protein in ameloblastoma and tooth germ. MATERIAL AND METHODS: Ep-CAM (MOC-31) expression was evaluated by immunohistochemistry in tooth germs (TG) (n = 16) ameloblastomas (AM) (n = 60) and 2 ameloblastic carcinomas. Sections were visualized in their totality with an optical microscope, and positivity observed in cell membrane and cytoplasm was graded according to the following semi-quantitative scale: Neg, "essentially unstained", for negative sections or staining <5% of cells; + for staining of 5-50% of cells; ++ for staining >50% of cells. RESULTS: Most tooth germs expressed MOC-31 (81.3%), strong staining was observed both in the inner epithelium of the enamel organ and in the adjacent stellate reticulum. 16.7% of the AM cases showed MOC-31 expression, the immunoexpression expression was diffuse at the cytoplasmic and membrane level. The only two cases of ameloblastic carcinoma included were strong positive to MOC-31. No correlation was observed between protein expression and gender, age, clinical variants, or histological subtypes. CONCLUSIONS: Overexpression was found in TG and ameloblastic carcinoma compared to AM; further studies with different experimental strategies are suggested to clarify the biological significance of this finding.

Anthropogenic eutrophication of Lake Titicaca (Bolivia) revealed by carbon and nitrogen stable isotopes fingerprinting.

Cultural eutrophication is the leading cause of water quality degradation worldwide. The traditional monitoring of eutrophication is time-consuming and not integrative in space and time. Here, we examined the use of carbon (δ13C) and nitrogen (δ15N) isotopic composition to track the degree of eutrophication in a bay of Lake Titicaca impacted by anthropogenic (urban, industrial and agricultural wastewater) discharges. Our results show increasing δ13C and decreasing δ15N signatures in macrophytes and suspended particulate matter with distance to the wastewater source. In contrast to δ15N and δ13C signatures, in-between aquatic plants distributed along the slope were not only affected by anthropogenic discharges but also by the pathway of carbon uptake, i.e., atmospheric (emerged) vs aquatic (submerged). A binary mixing model elaborated from pristine and anthropogenic isotope end-members allowed the assessment of anthropogenically derived C and N incorporation in macrophytes with distance to the source. Higher anthropogenic contribution was observed during the wet season, attributed to enhanced wastewater discharges and leaching of agricultural areas. For both seasons, eutrophication was however found naturally attenuated within 6 to 8 km from the wastewater source. Here, we confirm that carbon and nitrogen stable isotopes are simple, integrative and time-saving tools to evaluate the degree of eutrophication (seasonally or annually) in anthropogenically impacted aquatic ecosystems.

Genetic regulation of the ompX porin of Salmonella Typhimurium in response to hydrogen peroxide stress.

BACKGROUND: Salmonella Typhimurium is a Gram-negative pathogen that causes a systemic disease in mice resembling typhoid fever. During its infective cycle, S. Typhimurium is phagocytized by macrophages and proliferates inside a Salmonella-containing vacuole where Salmonella is exposed and survives oxidative stress induced by H2O2 through modulation of gene expression. After exposure of Salmonella to H2O2, the expression of the porin-encoding gene ompX increases, as previously shown by microarray analysis. Expression of ompX mRNA is regulated at a post-transcriptional level by MicA and CyaR sRNAs in aerobiosis. In addition, sequence analysis predicts a site for OxyS sRNA in ompX mRNA. RESULTS: In this work we sought to evaluate the transcriptional and post-transcriptional regulation of ompX under H2O2 stress. We demonstrate that ompX expression is induced at the transcriptional level in S. Typhimurium under such conditions. Unexpectedly, an increase in ompX gene transcript and promoter activity after challenges with H2O2 does not translate into increased protein levels in the wild-type strain, suggesting that ompX mRNA is also regulated at a post-transcriptional level, at least under oxidative stress. In silico gene sequence analysis predicted that sRNAs CyaR, MicA, and OxyS could regulate ompX mRNA levels. Using rifampicin to inhibit mRNA expression, we show that the sRNAs (MicA, CyaR and OxyS) and the sRNA:mRNA chaperone Hfq positively modulate ompX mRNA levels under H2O2-induced stress in Salmonella during the exponential growth phase in Lennox broth. CONCLUSIONS: Our results demonstrate that ompX mRNA is regulated in response to H2O2 by the sRNAs CyaR, MicA and OxyS is Salmonella Typhimurium.

Association of bilateral oophorectomy and menopause hormone therapy with mild cognitive impairment: the REDLINC X study.

BACKGROUND: Dementia is a major public health problem. Estrogen is a regulator of the central nervous system and its deficit could be involved in cognitive decline in older women. OBJECTIVE: This study aimed to evaluate the association of bilateral oophorectomy, menopause hormone therapy (MHT) and other factors on mild cognitive impairment (MCI). METHOD: The case-control study included 941 otherwise healthy postmenopausal women aged 60 years and over from six Latin American countries. Personal and family data were recorded and MCI was assessed using the Montreal Cognitive Assessment test (MoCA). RESULTS: Average age, years of education and body mass index were 66.1 ± 5.8 years, 12.4 ± 5.0 years and 26.0 ± 4.3 kg/m2, respectively. A total of 30.2% had undergone bilateral oophorectomy and 40.3% had used MHT. A total of 232 women (24.7%) had MCI. The prevalence of MCI was higher in women with intact ovaries and non-MHT users as compared to MHT users (29.3% vs. 11.7% [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.20-0.51]). Among oophorectomized women, MCI prevalence was higher among non-MHT users as compared to MHT users (45.2% vs. 12.8% [OR 0.18; 95% CI 0.10-0.32]). Logistic regression analysis determined that the variables associated with MCI were age >65 years (OR 1.69; 95% CI 1.20-2.38), parity (having >2 children; OR 1.69; 95% CI 1.21-2.37), bilateral oophorectomy (OR 1.56; 95% CI 1.09-2.24), hypertension (OR 1.41; 95% CI 1.01-1.96), being sexually active (OR 0.56; 95% CI 0.40-0.79), education >12 years (OR 0.46; 95% CI 0.32-0.65) and MHT use (OR 0.31; 95% CI 0.21-0.46). CONCLUSION: Age, parity, bilateral oophorectomy and hypertension are independent factors associated with MCI; contrary to this, higher educational level, maintaining sexual activity and using MHT are protective factors.

Genetic regulation of the ompX porin of Salmonella Typhimurium in response to hydrogen peroxide stress

BACKGROUND: Salmonella Typhimurium is a Gram negative pathogen that causes a systemic disease in mice resembling typhoid fever. During its infective cycle, S. Typhimurium is phagocytized by macrophages and proliferates inside a Salmonella containing vacuole where Salmonella is exposed and survives oxidative stress induced by H2O2 through modulation of gene expression. After exposure of Salmonella to H2O2, the expression of the porin encoding gene ompX increases, as previously shown by microarray analysis. Expression of ompX mRNA is regulated at a post transcriptional level by MicA and CyaR sRNAs in aerobiosis. In addition, sequence analysis predicts a site for OxyS sRNA in ompX mRNA. RESULTS: In this work we sought to evaluate the transcriptional and post transcriptional regulation of ompX under H2O2 stress. We demonstrate that ompX expression is induced at the transcriptional level in S . Typhimurium under such conditions. Unexpectedly, an increase in ompX gene transcript and promoter activity after challenges with H2O2 does not translate into increased protein levels in the wild type strain, suggesting that ompX mRNA is also regulated at a post transcriptional level, at least under oxidative stress. In silico gene sequence analysis predicted that sRNAs CyaR, MicA, and OxyS could regulate ompX mRNA levels. Using rifampicin to inhibit mRNA expression, we show that the sRNAs (MicA, CyaR and OxyS) and the sRNA:mRNA chaperone Hfq positively modulate ompX mRNA levels under H2O2 induced stress in Salmonella during the exponential growth phase in Lennox broth. CONCLUSIONS: Our results demonstrate that ompX mRNA is regulated in response to H2O2 by the sRNAs CyaR, MicA and OxyS is Salmonella Typhimurium.

Development of a Controlled Continuous Low-Dose Feeding Process.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 µm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.

Microbial mortality behavior promoted by silver (Ag+/Ago)-modified zeolite-rich tuffs for water disinfection.

BACKGROUND: In developing countries, death due to diseases caused by fecal-oral ingestion can be avoided by taking action on drinking water issues. Adequate access to water treatment systems to reduce infections is a critical cause. Silver has been used as an antibacterial product, including biomedical applications. Therefore, in this paper, the effect of the chemical speciation of silver from silver-modified zeolite-rich tuffs on the mortality of Escherichia coli (E. coli), Streptococcus faecalis (S. faecalis) and Candida albicans (C. albicans) suspended in aqueous solution was investigated for disinfection purposes. METHODS: The following aspects were considered to develop the investigation: a) the technique to prepare the modified zeolitic materials, either with ionic silver or silver nanoparticles, which were obtained in two ways: one, with grapefruit extract and the second, by using non-thermal plasma generated in a dielectric barrier discharge reactor of parallel plates; b) the response of the prokaryotes (bacteria) and eukaryote (yeast) microorganisms to disinfectant agents in batch systems; c) the disinfection processes as a function of time to obtain kinetics parameters; and d) the kinetics of the silver release from the silver-modified zeolite-rich tuffs, considering the models of Higuchi and Korsmeyer. The zeolitic materials were characterized by low-vacuum scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). RESULTS: The non-thermal plasma reduced ionic silver is more efficient at generating silver compounds with several oxidation states, which are essential during the microbial inhibition process. For the bacterial (E. coli and S. faecalis), the materials with nanoparticles were efficient to inactivate them. However, the yeast (C. albicans) reaches the total inactivation when the zeolitic material contains ionic silver in the crystalline network. CONCLUSION: The E. coli, S. faecalis and C. albicans survival behavior suspended in aqueous solutions after contact with Ag-modified natural zeolites depends on the chemical speciation of the silver present in these materials, Ag+1 in the case of OAgiZ or nanoparticles of Ago promoted by the grapefruit extract (OAgnpTZ), as well as by non-thermal plasma generated in a dielectric barrier discharge reactor of parallel plates (OAgnpPZ). In general, the concentration of silver in the aqueous solution after the disinfection process cannot exceed the recommended levels established for international organizations. The OAgnpPZ is a potential microbicide agent against E. coli and C. albicans, and the OAgn pTZ for F. faecalis.Graphical abstractARTWORK.

Performance Evaluation of a High-Precision Low-Dose Powder Feeder.

Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system. The current micro-feeder system is a volumetric feeder combined with a weighing balance at the outlet that measures feeder output rates. Feeding results are shown as a so-called "displacement-feed factor" curve for each material. Since the powder mass and volume are known in the micro-feeder system, in this work, we characterized an observed density variation during processing via a "displacement-feed factor" profile for each of the fed powders. This curve can be later used for calibrating the system to ensure an accurate, constant feed rate and in addition predicting feeding performance for that material at any feed rate. There is a relation between powder properties and feeding performance. Powders with finer particles and higher compressibility show densification during their feeding process. However, powders with larger particles and lower compressibility show both "densification" and "powder bed expansion," which is the manifestation of dilation and elastic recovery of particles during the micro-feeding process. Through the application of the displacement-feed factor, it is possible to provide precise feeding accuracy of low-dose materials.

Political partisanship and mobility restriction during the COVID-19 pandemic.

OBJECTIVES: Non-pharmaceutical interventions (NPIs) are effective in curbing the spread of severe acute respiratory syndrome coronavirus 2. All US states have adopted NPI policies, but the compliance to these measures and influence of sociopolitical factors on NPI adherence is unknown. NPI adherence may be approximated by personal mobility in a population that is tracked by anonymous mobile phone data. STUDY DESIGN: This is a cross-sectional study of state-level mobility changes across the US. METHODS: State-level mobility was based on anonymous mobile phone data from multiple participating carriers collected by the University of Washington's Institute for Health Metrics and Evaluation (http://www.healthdata.org). Pearson's correlation coefficient was used to examine the strength and direction of the relationship between political affiliations and mobility restriction across states. Multivariable linear regression analyses were used to assess other factors that may impact personal travel. RESULTS: All states experienced a decline in personal mobility but had varying nadirs ranging from a 34% to a 69% reduction in mobility, which was not temporally related to the timing of state-level NPI measures. There was a statistically significant linear and negative correlation (r = -0.79) between the proportion of Republicans/leaning Republicans and NPI adherence across US states. The negative association between Republicans and NPI adherence was significant even when adjusting for urbanization, proportion of essential workers, population, Gini index, and poverty rates. CONCLUSIONS: Political orientation affects risk perception, which may contribute to the unwillingness of some individuals to perceive the coronavirus disease 2019 pandemic as a risk and to comply with NPIs. Our results highlight the importance of sociopolitical factors in disease control and emphasize the importance of bipartisan efforts in fighting the pandemic. These results may have implications for the development, dissemination, and communication of public health policies.

Mixing Cell: a Device to Mimic Extent of Lubrication and Shear in Continuous Tubular Blenders.

Continuous manufacturing (CM) has clear potential for manufacturing solid oral dosages. It provides several advantages that may aid the manufacturing and quality of drug products. However, one of the main challenges of this technology is the relatively large amount of knowledge required and the amounts of material needed to develop the process during the early stages of development. Early process development evaluations of continuous manufacturing equipment often require larger amounts of material compared with batch, which hinder CM prospect for drugs during the early stages of process development. In this work, a small-scale evaluation of the mixing process occurring in a continuous mixing system was performed. The evaluation involved the use of a small-scale "mixing cell" which was able to replicate the lubrication process of a continuous mixer. It is worth mentioning that we designed the mixing cell by reconfiguration of an existing continuous tubular blender. The extent of lubrication evaluation was performed for three example formulations and was done by mimicking the amount of shear provided to a formulation by means of matching the number of paddle-passes that a formulation experiences within a continuous blending process in the batch mixing cell. The evaluation showed that the small-scale mixing cell was able to replicate the extent of lubrication-evaluated by measuring the tensile strength of compacts being made with both the continuous and mixing cell experiments-occurring in the continuous mixer using a fraction of the amount of materials needed to perform the same evaluation in the continuous blending process.

Depresión y ansiedad en mujeres histerectomizadas no oncológicas posterior a la cirugía / Depression and anxiety in non-cancer hysterectomized women after surgery

RESUMEN Introducción y objetivo: La histerectomía es la segunda cirugía ginecológica más frecuente, después de la cesárea, afectando a un importante porcentaje de la población femenina, con un gran impacto emocional. El objetivo de esta revisión es describir las consecuencias psiquiátricas y sus factores predisponentes, en las mujeres histerectomizadas no oncológicas posterior a la cirugía. Material y métodos: Se incluyeron investigaciones en inglés, español y portugués, con un máximo de 15 años de antigüedad. Se excluyeron investigaciones realizadas en mujeres histerectomizadas oncológicas y/o con antecedentes psiquiátricos previos a la cirugía. Resultados: Posterior a la histerectomía por causa benigna, aparecen trastornos depresivos y/o ansiosos en las mujeres en frecuencias variadas. En el post-operatorio inmediato de la histerectomía, se reportan prevalencias de hasta un 84% para depresión y hasta un 92% para ansiedad, respectivamente. En cuanto a los factores que predisponen a la incidencia de estos problemas, se encuentran; la paridad relacionado con la cantidad de hijos engendrados y el deseo de tener más hijos, la nuliparidad, la edad, la falta de información y educación previa a la cirugía, la soledad y escaso apoyo familiar, los mitos y creencias sociales en torno al procedimiento, entre otros. Conclusiones: El significado social del útero y el enjuiciamiento que vive la mujer histerectomizada, son factores relevantes en la aparición de trastornos depresivos y/o ansiosos. La importancia de la educación es esencial para el afrontamiento eficaz por parte de la mujer en este procedimiento.

ABSTRACT Introduction and objective: Hysterectomy is the second most frequent gynecological surgery, after caesarean section, affecting an important percentage of the female population, with a great emotional impact. The objective of this review is to describe the psychiatric consequences and their predisposing factors in non-oncological hysterectomized women after surgery. Material and methods: Research was included in English, Spanish and Portuguese, with a maximum of 15 years old. We excluded investigations carried out in oncological hysterectomized women and / or with psychiatric antecedents prior to surgery. Results: After hysterectomy due to benign cause, depressive and / or anxious disorders appear in women at varied frequencies. In the immediate postoperative period of the hysterectomy, prevalences of up to 84% are reported for depression and up to 92% for anxiety, respectively. As for the factors that predispose to the incidence of these problems, they are found; parity related to the number of children conceived and the desire to have more children, nulliparity, age, lack of information and education prior to surgery, loneliness and poor family support, myths and social beliefs about the procedure, among others. Conclusions: The social meaning of the uterus and the judgment of the hysterectomized woman are relevant factors in the appearance of depressive and / or anxious disorders. The importance of education is essential for effective coping by women in this procedure.

Comparación de la conducta alimentaria en niños de diferentes establecimientos educacionales y estado nutricional / Comparison of food behavior among school children by educational establishment and nutritional status

RESUMEN La conducta alimentaria en escolares está dada por grandes cambios, en este periodo adquieren mayor relevancia los hábitos alimentarios que determinarán su alimentación futura. Objetivo: Comparar la conducta alimentaria en escolares de diferentes establecimientos educacionales según estado nutricional. Métodos: Estudio observacional transversal, se aplicó cuestionario de comportamiento de alimentación infantil a 270 madres/tutores de niños entre 6 a 8 años de colegios públicos, subvencionados y privados de Viña del Mar, Chile. Resultados: El 49,6% de los niños presentó mal- nutrición por exceso. Los niños con obesidad presentaron respuestas positivas a la ingesta alimentaria en situaciones de molestia, preocupación y enojo, no fueron exigentes al momento de introducir nuevos sabores y fueron rápidos para comer (p<0,05). Al diferenciar por establecimiento, sólo el colegio particular presenta diferencias entre los niños con distinto estado nutricional, tanto en dimensiones de sobre ingesta como de antiingesta (p <0,05). Conclusiones: Los escolares de 6 a 8 años no presentaron diferencias significativas en su conducta alimentaria, niños con obesidad se asociaron positivamente a conducta de proingesta. Los niños del colegio público mantuvieron la misma conducta alimentaria, independiente de su estado nutricional, evidenciando mayor riesgo a presentar malnutrición por exceso a futuro, a diferencia del colegio particular.

ABSTRACT Eating behavior in schoolchildren is marked by great changes. In this period, eating habits acquire greater relevance as they will determine future behaviors. Objective: To compare feeding behaviors among schoolchildren by school type and nutritional status. Methods: A cross-sectional observational study in which a child eating behavior questionnaire was applied to 270 mothers / guardians of children between 6 and 8 years from public, subsidized and private schools in Viña del Mar, Chile was conducted. Results: Nearly half (49.6%) of children had malnutrition due to excess. Children with obesity had positive responses to food intake in situations of discomfort, worry and anger, were not demanding when introduced to new flavors and were quick to eat (p <0.05). When comparing by establishment, differences between children by nutritional status were observed only in those attending private schools, in terms of excess-intake and anti-eating (p <0.05). Conclusions: Children from 6 to 8 years old did not present significant differences in their eating behavior, children with obesity reported pro-eating behavior. Children attending public schools maintained the same eating behavior, independent of their nutritional status, showing a higher risk of malnutrition due to excess in the future, unlike those attending private school.

Economic evaluation of sunitinib versus pazopanib and best supportive care for the treatment of metastatic renal cell carcinoma in Chile: cost-effectiveness analysis and a mixed treatment comparison.

Background: Sunitinib and Pazopanib are two metastatic renal cell carcinoma (MRCC) treatment alternatives, however the health system in Chile does not consider coverage for any. The cost-effectiveness versus relevant comparator was assessed to support evidence-based decision making. Methods: A four health states Markov model was built: first, second line treatments, BSC and death. Benefits were measured in QALYs, and efficacy estimates were obtained from an indirect treatment comparison. A 10-year time horizon and a 3% undifferentiated discount rate were considered. Deterministic and probabilistic sensitivity analyses were performed. Results: The costs of treating MRCC with Sunitinib were higher than Pazopanib and BSC. When comparing Sunitinib versus Pazopanib, the incremental benefit is small favoring Sunitinib (0.03 QALYs). The base case scenario shows an average ICER of PA versus BSC of US$62,327.11/QALY and of US$85,885/QALY for Sunitinib versus Pazopanib. The ICER was most sensitive to the OS relative to BSC, where evidence was associated to important bias. Conclusions: Sunitinib or Pazopanib can be considered cost-effective if a 3 GDP per-capita threshold is assumed. The decision between SU or PA is highly sensitive to the price of the drugs, rather than the outcomes. Therefore, the decision might be made based on cost-minimization exercise.