13 research outputs found
Assessing role of lipid and polymer based delivery systems in inserts
No full textMajority of gynaecological, proctologic diseases were treated through rectal or vaginal delivery of medications, which can bypass the first pass metabolism and can produce required local effect. Inserts are evolutionary pharmaceutical dosageform that are semi solid at room temperature but upon insertion in cavities of humans, melt and release the drug localised. The inserts are advantageous since they can be placed at scare sites where blood perfusion is high that can enable for rapid absorption limiting many side effects. Ocular inserts represents the advanced technology in treating several ophthalmic diseases. Designing and development of optimum inserts is a challenge ever faced by Pharmaceutical researchers. In view of this, lipid and polymer based systems were additionally employed to improve the therapeutic efficiency of foresaid dosage forms. The review rationalises the importance of these inserts and their broad applications for multidisciplinary applications
Assessing role of lipid and polymer based delivery systems in inserts
No full textMajority of gynaecological, proctologic diseases were treated through rectal or vaginal delivery of medications, which can bypass the first pass metabolism and can produce required local effect. Inserts are evolutionary pharmaceutical dosageform that are semi solid at room temperature but upon insertion in cavities of humans, melt and release the drug localised. The inserts are advantageous since they can be placed at scare sites where blood perfusion is high that can enable for rapid absorption limiting many side effects. Ocular inserts represents the advanced technology in treating several ophthalmic diseases. Designing and development of optimum inserts is a challenge ever faced by Pharmaceutical researchers. In view of this, lipid and polymer based systems were additionally employed to improve the therapeutic efficiency of foresaid dosage forms. The review rationalises the importance of these inserts and their broad applications for multidisciplinary applications
A multi-country analysis of COVID-19 hospitalizations by vaccination status
No full textBackground: Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes. Methods: Here, we use data from an international consortium to study this question and assess whether differences between these groups are context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed. Findings: While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed. Conclusions: These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history. Funding: This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill & Melinda Gates Foundation (OPP1209135); and the philanthropic support of the donors to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section
Long Covid: a global health issue – a prospective, cohort study set in four continents
No full textIntroduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to <6 and 6 to <12 months post-hospital discharge. A standardised case report form developed by International Severe Acute Respiratory and emerging Infection Consortium’s Global COVID-19 Follow-up working group evaluated the frequency of fever, persistent symptoms, breathlessness (MRC dyspnoea scale), fatigue and impact on daily activities.Results Of 11 860 participants (median age: 52 (IQR: 41–62) years; 52.1% females), 56.5% were from HICs and 43.5% were from LMICs. The proportion identified with Long Covid was significantly higher in HICs vs LMICs at both assessment time points (69.0% vs 45.3%, p<0.001; 69.7% vs 42.4%, p<0.001). Participants in HICs were more likely to report not feeling fully recovered (54.3% vs 18.0%, p<0.001; 56.8% vs 40.1%, p<0.001), fatigue (42.9% vs 27.9%, p<0.001; 41.6% vs 27.9%, p<0.001), new/persistent fever (19.6% vs 2.1%, p<0.001; 20.3% vs 2.0%, p<0.001) and have a higher prevalence of anxiety/depression and impact on usual activities compared with participants in LMICs at 2 to <6 and 6 to <12 months post-COVID-19 hospital discharge, respectively.Conclusion Our data show that Long Covid affects populations globally, manifesting similar symptomatology and impact on functioning in both HIC and LMICs. The prevalence was higher in HICs versus LMICs. Although we identified a lower prevalence, the impact of Long Covid may be greater in LMICs if there is a lack of support systems available in HICs. Further research into the aetiology of Long Covid and the burden in LMICs is critical to implement effective, accessible treatment and support strategies to improve COVID-19 outcomes for all
An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients
No full textBackground: Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings.
Methods: Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries.
Results: Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61-0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population.
Conclusions: Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome
Synthetic quinoline alkaloid and limonoid (triterpene) -type compounds with anti-leishmania potential: an approach to the mechanism of action
No full textLa leishmaniasis es una enfermedad parasitaria antropozoonótica, causada por el protozoario del género Leishmania spp. y transmitida por el mosquito del genero Lutzomya. Dentro de las formas clínicas de la enfermedad, la cutánea, constituye la manifestación mas frecuente en el mundo, y corresponde a más del 90% de los casos resportados en Colombia y en el mundo. Una de las dificultades más evidentes en el control de esta enfermedad, ha sido el tratamiento, el cual además de haber reportado pérdida de eficacia, presenta efectos adversos, largos esquemas de tratamiento y formas de administración de baja adherencia por parte del paciente, que generan el abandono del mismo y la generación de cepas resistentes. Por esta razón, la búsqueda de alternativas terapéuticas de aplicación tópica constituye una necesidad de alta prioridad, para disminuir el problema de salud pública que conlleva esta enfermedad.
De este modo, en estudios previos realizados en el Grupo de Investigación en Inmunotoxicologia se identificaron dos moléculas de origen vegetal con propiedades antileishmaniales, correspondientes a alcaloides quinolínicos (N-metil-8-metoxiflindersina) y triterpenoides de tipo limonoide (11α,19β-dihidroxi-7-acetoxi-7-deoxoichangina), con efecto directo frente al parásito y propiedades inmunoduladoras en células humanas infectadas por el parásito; sin embargo, el origen (a partir de material vegetal de Raputia heptaphylla) y las dificultades que conllevan la extracción y la purificación, conllevó al diseño de estrategias para encontrar moléculas con características estructurales afines, bajo el principio de propiedades similares (PPS).
Entre los hallazgos mas relevantes obtenidos en este trabajo, se encuentran los resultados obtenidos con compuestos de origen sintético y análogos a las moléculas naturales, los cuales fueron seleccionados por medio de estrategias In silico: triterpenoides [ácido oleanólico (5), glicirrizato de amonio (7) y ácido 18B-glicirretínico (8)] y alcaloides quinolínicos [1,2,3,4-tetrahidro-(benzo)-3-qinolin-ol (13) y 2-amino-8-hidroxiquinolina (19)] los cuales presentaron actividad anti-leishmanial In vitro [sobre promastigotes (13 y 19) y amastigotes intracelulares de L. (V.) panamensis (5, 7, 8, 13 y 19)] e In vivo [promoviendo la cura clínica (entre un 20% (8), 33,3% (13) y 50% (19) los animales cicatrizan completamente la lesión) y mejoría clínica (100% (5), 80% (7), 60% (8), 66,6% (13) y 33.3% (19), reducción en al menos un 20% el tamaño de la lesión), de los animales tratados con los compuestos, administrados de forma tópica].
De acuerdo con los efectos de cada compuesto, se propusieron modelos de aproximación al modo de acción de cada molécula. Los triterpenoides 5 y 7 mostraron característica de pro-fármacos (actividad evidente sobre la foma amastigote en MdMhu infectados), pero con afectaciones diferenciales en el amastigote intracelular para el triterpenoide 5 [causa muerte de tipo necrosis (presencia de membranas hinchadas o alteradas, acidocalcisomas y daño nuclear)] y saponina 7 [(afinidad por la mitocondria de MdMhu y parásitos (causando en Leishmania spp. estrés celular, la parición de acidocalcisomas e hinchamiento de membranas celulares)]. El triterpenoide 8 indujo el incremento diferencial de NO, a través de la modulación de iNOS vía NF-kB en macrófagos infectados y modificaciones en los amastigotes (citoquinesis alterada y señales de apoptosis).
Se resaltan los hallazgos de los compuestos alcaloides (13 y 19), los cuales fueron activos frente a los dos estadios del parásito (promastigotes y amastigotes). El alcaloide 13, actúa sobre reservas de lípidos y componentes de membrana [(reflejado en el aumento de cuerpos lipídicos y vacuolas parasitóforas comunales en MdMhu)], causando el estrés celular de los parásitos (presencia de acidocalcisomas y citoquinesis alterada) y la disminución de la carga parasitaria en estas células, induciendo el aumento temprano de ROS en MI, contribuyendo así con el control temprano del parásito. Mientras que el efecto del compuesto 19 está dirigido hacia la modulación de procesos de generación de energía y respiración oxidativa (producción de especies reactivas en promastigotes y despolarización de la mitocondria), los cuales conducen a los parásitos a la muerte de tipo apoptosis (hinchamiento de membranas celulares, presencia de acidocalcisomas y distribución anormal de cromatina) y que se asocian con la expresión diferencial de proteínas (spots) en amastigotes expuestos al alcaloide; mientras que en las células hospederas infectadas, se induce apoptosis, mostrando la selectividad del compuesto.
Estos resultados permiten soportar nuestro modelo de búsqueda de compuestos, en donde a partir de moléculas de difícil obtención (origen vegetal), se pueden encontrar antileishmaniales promisorios. Se destaca, que para cada molécula antiparasitaria encontrada en este proyecto, se identificó un posible modo de acción en el modelo de células primarias, así como su efectividad terapéutica en un modelo In vivo; estos hallazgos contribuyen al entendimiento de la forma de actuación de este tipo de compuestos y abre el camino para la optimización y tratamiento de la leishmaniasis cutánea en el país.Leishmaniasis is an anthroponotic parasitic disease, caused by the protozoan of the genus Leishmania spp. and transmitted by the mosquito of the genus Lutzomya. This disease has been classified as a neglected pathology by the WHO because its presence is established in tropical and sub-tropical areas and mainly in developing countries. Within the clinical forms of the disease, the cutaneous form constitutes the most frequent manifestation in the world, which corresponds to more than 90% of the cases reported in Colombia and the world. One of the most obvious difficulties in the control of this disease has been treated, which is accompanied by adverse effects, long treatment schedules, and forms of administration that are not very friendly to the patient, which generate the abandonment of treatment and the generation of resistant strains. For this reason, the search for therapeutic alternatives for topical application constitutes an imperative need to mitigate the public health problem that this disease entails. Thus, in previous studies carried out by the Immunotoxicology research group, two molecules with antileishmanial properties were identified, corresponding to quinolinic alkaloids (N-methyl-8-methoxyflindersine) and limonoid-type triterpenoids (11α, 19βdihydroxy-7- acetoxy-7-deoxoichangin), with direct effect against the parasite and immunomodulatory properties in human cells infected by the parasite; however, the origin (from Raputia heptaphylla plant material) and the difficulties involved in extraction and purification, led to the design of strategies to find molecules with similar structural characteristics, under the principle of similar properties (PPS). Among the most relevant findings obtained in this work, are the results obtained with the five compounds of synthetic origin and analogous to natural molecules (previously evaluated by the research group), which were selected through the In silico strategies: Triterpenoid compounds [oleanolic acid (5), ammonium glycyrrhizate (7) and 18B-glycyrrhetinic acid (8)] and quinolinic alkaloids [1,2,3,4-tetrahydro- (benzo) -3-qinolin-ol (13) and 2-amino-8- hydroxyquinoline (19); which presented anti-leishmanial activity In vitro [on promastigotes (13 and 19) and intracellular amastigotes of L. (V.) panamensis (5, 7, 8, 13 and 19)] and In vivo [promoting clinical cure (between 20% (8), 33.3% (13) and 50% (19) the animals completely heal the lesion) and clinical improvement (100% (5), 80% (7), 60% (8), 66,6% (13) and 33.3% (19), reduction of lesion size by at least 20%), of the animals treated with the compounds, administered topically]. Each synthetic antileishmanial compound showed evident effects in the model used, giving rise to models of approximation to its mode of action. Triterpenoids 5 and 7 showed prodrug activity [(Activity in the amastigote form), in addition to causing necrosis-type death in the intracellular parasite (presence of swollen or altered membranes, acidocalcisomes, and nuclear damage) by the compound 5, while saponin 7 had an evident affinity for the mitochondria of MdMhu and parasites (causing cellular stress, the calving of acidocalcisomes and swelling of cell membranes in Leishmania spp.)]. Triterpenoid 8 (synthetic pentacyclic) revealed immunomodulatory properties by inducing the differential increase in NO, through modulation of iNOS via NF-kB in infected macrophages and evident alterations in amastigotes (altered cytokinesis and apoptosis signals), possibly as an effect of NO. The findings of the alkaloid compounds (13 and 19) are highlighted, which had evident activity against the two stages of the parasite (promastigotes and amastigotes). The alkaloid 13 acts on lipid reserves and membrane components [(reflected in the increase of lipid bodies and communal parasitophorous vacuoles in MdMhu)], causing cellular stress of the parasites (presence of acidocalcisomes and altered cytokinesis) and the decrease of the parasite load in these cells inducing the early increase of ROS in MI, contributing to the early control of the parasite. The effect of compound 19 evidenced in intracellular promastigotes and amastigotes is directed towards the modulation of processes of energy generation and oxidative respiration (production of reactive species in promastigotes and depolarization of the mitochondria), which lead parasites to death of the type apoptosis (swelling of cell membranes, presence of acidocalcisomes and abnormal chromatin distribution) and that are associated with the differential expression of proteins (spots) in amastigotes exposed to the alkaloid; while in host cells, the induction of early apoptosis was differentially evidenced in infected cells, showing the selectivity of the compound. These results allow us to support our compound search model, where promising antileishmanial can be found from difficult-to-obtain molecules (plant origin). It should be noted that for each antiparasitic molecule found in this project, a possible mode of action was identified in the primary cell model, as well as its therapeutic effectiveness in an In vivo model; These findings contribute to the understanding of how this type of compound works and opens the way for the optimization and treatment of cutaneous leishmaniasis in the country.Ministerio de ciencia, tecnología e innovación de Colombia (Minciencias)DoctoradoDoctora en BiotecnologíaDesarrollo de alternativas terapéuticas frente a enfermedades tropicale
Long-term neurological symptoms after acute COVID-19 illness requiring hospitalization in adult patients: insights from the ISARIC-COVID-19 follow-up study
No full textin this study we aimed to characterize the type and prevalence of neurological symptoms related to neurological long-COVID-19 from a large international multicenter cohort of adults after discharge from hospital for acute COVID-19
Global, regional and national burden of dietary iron deficiency from 1990 to 2021: a Global Burden of Disease study
No full text: Although iron deficiency is well documented, less is known about dietary involvement in symptomatic iron deficiency manifesting in medical conditions. In this study, we quantified the global burden of dietary iron deficiency, focusing on where inadequate dietary iron intake leads to clinical manifestations such as anemia. We analyzed data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to estimate dietary iron deficiency prevalence and disability-adjusted life years (DALYs), stratified by age, sex, geography and socio-demographic index (SDI) across 204 countries. In 2021, global age-standardized prevalence and DALY rates were 16,434.4 (95% uncertainty interval (UI), 16,186.2-16,689.0) and 423.7 (285.3-610.8) per 100,000 population, with rates decreasing by 9.8% (8.1-11.3) and 18.2% (15.4-21.1) from 1990 to 2021. A higher burden was observed in female individual (age-standardized prevalence, 21,334.8 (95% UI, 20,984.8-21,697.4); DALYs, 598.0 (402.6-854.4)) than in male individual ((age-standardized prevalence, 11,684.7 (11,374.6-12,008.8); DALYs, 253.0 (167.3-371.0)). High-SDI countries presented greater improvement, with a 25.7% reduction compared to 11.5% in low-SDI countries. Despite global improvements, dietary iron deficiency remains a major health concern with a global prevalence of 16.7%, particularly affecting female individuals, children and residents in low-SDI countries. Urgent interventions through supplementation, food security measures and fortification initiatives are essential
Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study
No full textBackground: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs).
Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support.
Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]).
Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable
Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after coronavirus disease 2019 hospitalization: an international multi-centre prospective observational study
No full text: Although it is known that coronavirus disease 2019 can present with a range of neurological manifestations and in-hospital complications, sparse data exist on whether these initial neurological symptoms of coronavirus disease 2019 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; PANSC) and whether female versus male sex impacts symptom resolution. In this international, multi-centre, prospective, observational study across 407 sites from 15 countries (30 January 2020 to 30 April 2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time. PANSC symptoms included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia and muscle ache/joint pain, on which information was collected at index hospitalization and during follow-up assessments. The analysis considered a time to the resolution of individual and all neurological symptoms. The resulting times were modelled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. The model results were summarized as cumulative probability functions and age-adjusted and sex-adjusted median times to resolution. We included 6862 hospitalized adults with coronavirus disease 2019, who had follow-up assessments. The median age of the participants was 57 years (39.2% females). Males and females had similar baseline characteristics, except that more males (versus females) were admitted to the intensive care unit (30.5 versus 20.3%) and received mechanical ventilation (17.2 versus 11.8%). Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median = 102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. The reported prevalence in females was generally higher (versus males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, although fatigue, altered consciousness and myalgia remained unresolved in >10% of the cohort. Females had a longer time to the resolution (5.2 versus 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom. In the multivariable analysis, males were associated with a shorter time to the resolution of symptoms (hazard ratio = 1.53; 95% confidence interval = 1.39-1.69). Intensive care unit admission was associated with a longer time to the resolution of symptoms (hazard ratio = 0.68; 95% confidence interval = 0.60-0.77). Post-discharge stroke was uncommon (0.3% in females and 0.5% in males). Despite the methodological challenges involved in the collection of survey data, this international multi-centre prospective cohort study demonstrated that PANSC following index hospitalization was high. Symptom prevalence was higher and took longer to resolve in females than in males. This supported the fact that while males were sicker during acute illness, females were disproportionately affected by PANSC
