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Retrospective cohort studies in Cameroon found an association between Onchocerca volvulus microfilarial load in childhood (measured in 1991-1993) and risk of developing epilepsy later in life (measured in 2017). We parameterised and integrated this relationship (across children aged 3-15 years) into the previously published, stochastic transmission model, EPIONCHO-IBM, for Simulium damnosum sensu lato-transmitted onchocerciasis. We simulated 19 years (1998-2017) of annual ivermectin mass drug administration (MDA) reflecting coverage in the study area, and modelled epilepsy prevalence and incidence. Scenario-based simulations of 25 years of (annual and biannual) MDA in hyper- and holoendemic settings, with 65% and 80% therapeutic coverage, were also conducted. EPIONCHO-IBM predicted 7.6% epilepsy prevalence (compared to 8.2% in the Cameroon study) and incidence of 317 cases/100,000 person-years (compared to 350). In hyperendemic areas, 25 years of biannual MDA (80% coverage) eliminated onchocerciasis-associated epilepsy (OAE) and protected untreated under-fives from its development. Strengthening onchocerciasis programmes, implementing alternative strategies, and evaluating treatment for under-fives and school-age children are crucial to prevent OAE in highly-endemic settings.
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Epilepsia , Ivermectina , Onchocerca volvulus , Oncocercosis , Ivermectina/uso terapéutico , Oncocercosis/epidemiología , Oncocercosis/tratamiento farmacológico , Oncocercosis/complicaciones , Humanos , Niño , Epilepsia/epidemiología , Epilepsia/tratamiento farmacológico , Epilepsia/parasitología , Adolescente , Preescolar , Prevalencia , Incidencia , Camerún/epidemiología , Animales , Femenino , Masculino , Onchocerca volvulus/efectos de los fármacos , Administración Masiva de Medicamentos , Estudios Retrospectivos , Simuliidae/parasitologíaRESUMEN
Plasmodium falciparum is the causative agent of malaria and remains a pathogen of global importance. Asexual blood stage replication, via a process called schizogony, is an important target for the development of new antimalarials. Here we use ultrastructure-expansion microscopy to probe the organisation of the chromosome-capturing kinetochores in relation to the mitotic spindle, the centriolar plaque, the centromeres and the apical organelles during schizont development. Conditional disruption of the kinetochore components, PfNDC80 and PfNuf2, is associated with aberrant mitotic spindle organisation, disruption of the centromere marker, CENH3 and impaired karyokinesis. Surprisingly, kinetochore disruption also leads to disengagement of the centrosome equivalent from the nuclear envelope. Severing the connection between the nucleus and the apical complex leads to the formation of merozoites lacking nuclei. Here, we show that correct assembly of the kinetochore/spindle complex plays a previously unrecognised role in positioning the nascent apical complex in developing P. falciparum merozoites.
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Centrosoma , Cinetocoros , Plasmodium falciparum , Proteínas Protozoarias , Huso Acromático , Cinetocoros/metabolismo , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiología , Centrosoma/metabolismo , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/genética , Huso Acromático/metabolismo , Humanos , Merozoítos/metabolismo , Merozoítos/fisiología , Mitosis , Centrómero/metabolismo , Membrana Nuclear/metabolismo , Malaria Falciparum/parasitología , Malaria Falciparum/metabolismoRESUMEN
People who report frequently using cognitive reappraisal to decrease the impact of potentially upsetting situations report better affective functioning than people who report using cognitive reappraisal less frequently. However, most work linking everyday reappraisal use to affective outcomes has been correlational, making causal inference difficult. In this study, we examined whether 2 weeks of daily practice of reappraising negatively valenced personally relevant events would improve affective functioning compared with a wait-list control. Data were collected between 2021 and 2022 from a sample mainly comprised of females (82%) and who identified as Asian (35%) or White/Caucasian (40%). Our planned analyses indicated that reappraisal decreased depressive symptoms and perceived stress as well as increased life satisfaction both immediately and 4 weeks postintervention. Reductions in depressive symptoms and perceived stress were mediated by increases in reappraisal self-efficacy. These findings support the causal efficacy of brief reappraisal training. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.
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COVID-19 , Enfermedades Desatendidas , Medicina Tropical , Enfermedades Desatendidas/prevención & control , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Modelos Teóricos , Organización Mundial de la Salud , SARS-CoV-2 , Toma de Decisiones , Salud GlobalRESUMEN
A female patient in her 50s presented with abdominal pain, nausea and jaundice. She had a history of prior Roux-en-Y gastric bypass and her body mass index was 52.5 kg/m2 Biochemical testing revealed a total bilirubin level of 14.3 mg/dL (normal<1.2 mg/dL) and carbohydrate antigen 19-9 of 38.3 units/mL (normal<36.0 units/mL). CT demonstrated a 3.2 cm pancreatic head mass, biliary and pancreatic duct dilation and cystic replacement of the pancreas. The findings were consistent with a diagnosis of mixed-type intraductal papillary mucinous neoplasm (IPMN) with invasive malignancy. The patient's Roux-en-Y anatomy precluded endoscopic biopsy, and she underwent upfront resection with diagnostic laparoscopy, open total pancreatectomy, splenectomy and remnant gastrectomy with reconstruction. Pathology confirmed T2N1 pancreatic adenocarcinoma, 1/29 lymph nodes positive and diffuse IPMN. She completed adjuvant chemotherapy. IPMNs have malignant potential and upfront surgical resection should be considered without biopsy in the appropriate clinical setting.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Derivación Gástrica , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Femenino , Humanos , Adenocarcinoma/cirugía , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/diagnóstico , Gastrectomía , Pancreatectomía , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Esplenectomía , Persona de Mediana EdadRESUMEN
Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes' assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration. Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14 days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts. Results: Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3 years (range 24-80 years), and 67.4% (N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration. Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure.
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BACKGROUND: WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. METHODS: For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. FINDINGS: Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. INTERPRETATION: Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. FUNDING: The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. TRANSLATIONS: For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.
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Ivermectina , Administración Masiva de Medicamentos , Oncocercosis Ocular , Ivermectina/administración & dosificación , Ivermectina/uso terapéutico , Humanos , África del Sur del Sahara/epidemiología , Oncocercosis Ocular/epidemiología , Oncocercosis Ocular/prevención & control , Oncocercosis Ocular/tratamiento farmacológico , Animales , Oncocercosis/epidemiología , Oncocercosis/transmisión , Oncocercosis/prevención & control , Oncocercosis/tratamiento farmacológico , Erradicación de la Enfermedad , Control de Insectos/métodos , Antiparasitarios/administración & dosificación , Antiparasitarios/uso terapéuticoRESUMEN
BACKGROUND: Approximately 15% of patients experience post-hepatectomy liver failure after major hepatectomy. Poor hepatocyte uptake of gadoxetate disodium, a magnetic resonance imaging contrast agent, may be a predictor of post-hepatectomy liver failure. METHODS: A retrospective cohort study of patients undergoing major hepatectomy (≥3 segments) with a preoperative gadoxetate disodium-enhanced magnetic resonance imaging was conducted. The liver signal intensity (standardized to the spleen) and the functional liver remnant was calculated to determine if this can predict post-hepatectomy liver failure after major hepatectomy. RESULTS: In 134 patients, low signal intensity of the remnant liver standardized by signal intensity of the spleen in post-contrast images was associated with post-hepatectomy liver failure in multiple logistic regression analysis (Odds Ratio 0.112; 95% CI 0.023-0.551). In a subgroup of 33 patients with lower quartile of functional liver remnant, area under the curve analysis demonstrated a diagnostic accuracy of functional liver remnant to predict post-hepatectomy liver failure of 0.857 with a cut-off value for functional liver remnant of 1.4985 with 80.0% sensitivity and 89.3% specificity. CONCLUSION: Functional liver remnant determined by gadoxetate disodium-enhanced magnetic resonance imaging is a predictor of post-hepatectomy liver failure which may help identify patients for resection, reducing morbidity and mortality.
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Medios de Contraste , Gadolinio DTPA , Hepatectomía , Fallo Hepático , Imagen por Resonancia Magnética , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Fallo Hepático/etiología , Fallo Hepático/diagnóstico por imagen , Anciano , Factores de Riesgo , Resultado del Tratamiento , AdultoRESUMEN
PURPOSE: Risk factors of gallbladder cancer (GBC) are not well-defined resulting in greater than 60% of GBCs being diagnosed incidentally following cholecystectomy performed for presumed benign indications. As most localized GBCs require more extensive oncologic surgery beyond cholecystectomy, this study aims to examine factors associated with incidentally found GBC to improve preoperative and intraoperative diagnoses. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Database from 2007 to 2017 was used to identify cholecystectomies performed with and without a final diagnosis of GBC. Univariate and multivariable logistic regressions were used to compare demographic, intraoperative, and postoperative characteristics among those with and without a diagnosis of GBC. RESULTS: The incidence of GBC was observed to be 0.11% (441/403,443). Preoperative factors associated with risk of GBC included age > 60 (OR 6.51, p < .001), female sex (OR 1.75, p < .001), history of weight loss (2.58, p < .001), and elevated preoperative alkaline phosphatase level (OR 1.67, p = .001). Open approach was associated with 7 times increased risk of GBC compared to laparoscopic approach (OR 7.33, p < .001). In addition to preoperative factors and surgical approach, longer mean operative times (127 min vs 70.7 min, p < .001) were significantly associated with increased risk of GBC compared to benign final pathology. CONCLUSION: This study demonstrates that those with incidentally discovered GBC at cholecystectomy are unique from those undergoing cholecystectomy for benign indications. By identifying predictors of GBC, surgeons can choose high risk individuals for pre-operative oncologic evaluation and consider better tools for identifying GBC such as intraoperative frozen pathology.
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Colecistectomía , Neoplasias de la Vesícula Biliar , Hallazgos Incidentales , Humanos , Neoplasias de la Vesícula Biliar/epidemiología , Neoplasias de la Vesícula Biliar/cirugía , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/patología , Femenino , Masculino , Persona de Mediana Edad , Factores de Riesgo , Colecistectomía/efectos adversos , Colecistectomía/estadística & datos numéricos , Anciano , Incidencia , Estudios Retrospectivos , AdultoRESUMEN
BACKGROUND AND OBJECTIVES: The accepted approach to pain management following open pancreatoduodenectomy (PD) remains controversial, with the most recent enhanced recovery after surgery (ERAS) protocols recommending epidural anesthesia (EA). Few studies have investigated intrathecal (IT) morphine, combined with transversus abdominis plane (TAP) blocks. We aim to compare the different approaches to pain management for open PD. METHODS: Patients who underwent open PD at our institution from 2020 to 2022 were included in the study. Patient characteristics, pain management, and postoperative outcomes between EA, IT morphine with TAP blocks, and TAP blocks only were compared using univariate analysis. RESULTS: Fifty patients were included in the study (58% male, median age 66 years [interquartile range, IQR: 58-73]). Most patients received IT morphine (N = 24, 48%) or EA (N = 18, 36%). The TAP block-only group required higher doses of postoperative narcotics while hospitalized (p = 0.004) and at discharge (p = 0.017). The IT morphine patients had a shorter median time to Foley removal (p = 0.007). Postoperative pain scores, non-opioid administration, postoperative bolus requirements, postoperative outcomes, and length of stay were similar between pain modalities. CONCLUSIONS: IT morphine and EA showed comparable efficacy with superior results compared to TAP blocks alone. Integration of IT morphine into PD ERAS protocols should be considered.
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Anestesia Epidural , Morfina , Humanos , Masculino , Anciano , Femenino , Analgésicos Opioides , Pancreaticoduodenectomía/efectos adversos , Músculos Abdominales/cirugía , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Dolor Postoperatorio/prevención & controlRESUMEN
INTRODUCTION: Minority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. METHODS: Patients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. RESULTS: Of the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). CONCLUSIONS: Patients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.
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Adenocarcinoma , Disparidades en Atención de Salud , Hospitales , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/epidemiología , Adenocarcinoma/etnología , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Población Negra , Hospitales/estadística & datos numéricos , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/etnología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Disparidades en Atención de Salud/etnología , Disparidades en Atención de Salud/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricosRESUMEN
Presentation of the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (EMP1) at the surface of infected red blood cells (RBCs) underpins the malaria parasite's pathogenicity. The transport of EMP1 to the RBC surface is facilitated by a parasite-derived trafficking system, in which over 500 parasite proteins are exported into the host cell cytoplasm. To understand how genetic ablation of selected exported proteins affects EMP1 transport, several EMP1 surface presentation assays have been developed, including: 1) trypsinization of surface-exposed EMP1 and analysis by SDS-PAGE and immunoblotting; and 2) infected RBC binding assays, to determine binding efficiency to immobilized ligand under physiological flow conditions. Here, we describe a third EMP1 surface presentation assay, where antibodies to the ectodomain of EMP1 and flow cytometry are used to quantify surface-exposed EMP1 in live cells. The advantages of this assay include higher throughput capacity and data better suited for robust quantitative analysis. This protocol can also be applied to other cellular contexts where an antibody can be developed for the ectodomain of the protein of interest.
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Background: Patients with diabetes and obesity are at higher risk of adverse long-term outcomes following coronary artery bypass grafting. The use of bilateral internal thoracic arteries (BITA) can potentially offer survival benefit in higher risk patients compared to single internal thoracic artery (SITA), but BITA is not routinely used due to lack of clear evidence of efficacy and concerns over sternal wound complications. Methods: Medline, Embase and the Cochrane Library were searched for studies comparing the efficacy and safety of BITA and SITA grafting in patients with diabetes and obesity. Meta-analysis of mortality and sternal wound complications was performed. Results: We identified eight observational and ten propensity matched studies, and one RCT, comparing BITA and SITA which included patients with diabetes (n = 19,589); two propensity matched studies and one RCT which included patients with obesity (n = 6,972); mean follow up was 10.5 and 11.3 years respectively. Meta-analysis demonstrated a mortality reduction for BITA compared to SITA in patients with diabetes (risk ratio [RR] 0.79; 95% confidence interval [CI] 0.70-0.90; p = 0.0003). In patients with obesity there was a non-significant reduction in mortality in the BITA group (RR 0.73, 95% CI 0.47-1.12; p = 0.15). There was a significantly higher rate of sternal wound complications following BITA observed in patients with diabetes (RR 1.53, 95% CI 1.23-1.90; p = 0.0001) and obesity (RR 2.24, 95% CI 1.63-3.07; p < 0.00001). Conclusions: BITA is associated with better long-term survival in patients with diabetes. The effects of BITA grafting in patients with obesity are uncertain. BITA is associated with higher rates of sternal wound complications compared to SITA in both patients with diabetes and obesity.
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The malaria parasite uses actin-based mechanisms throughout its lifecycle to control a range of biological processes including intracellular trafficking, gene regulation, parasite motility and invasion. In this work we assign functions to the Plasmodium falciparum formins 1 and 2 (FRM1 and FRM2) proteins in asexual and sexual blood stage development. We show that FRM1 is essential for merozoite invasion and FRM2 is required for efficient cell division. We also observed divergent functions for FRM1 and FRM2 in gametocyte development. Conditional deletion of FRM1 leads to a delay in gametocyte stage progression. We show that FRM2 controls the actin and microtubule cytoskeletons in developing gametocytes, with premature removal of the protein resulting in a loss of transmissible stage V gametocytes. Lastly, we show that targeting formin proteins with the small molecule inhibitor of formin homology domain 2 (SMIFH2) leads to a multistage block in asexual and sexual stage parasite development.
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Actinas , Plasmodium falciparum , Actinas/genética , Forminas , Plasmodium falciparum/genética , División Celular , CitoesqueletoRESUMEN
M5717 is a promising antimalarial drug under development that acts against multiple stages of the life cycle of Plasmodium parasites by inhibiting the translation elongation factor 2 (PfeEF2), thereby preventing protein synthesis. The parasite clearance profile after drug treatment in preclinical studies in mice, and clinical trials in humans showed a notable delayed clearance phenotype whereby parasite infected red blood cells (iRBCs) persisted in the bloodstream for a significant period before eventual clearance. In a normal P. falciparum infection iRBCs sequester in the deep circulation by cytoadherence, allowing them to avoid surveillance and clearance in the spleen. We found that M5717 blocks parasite modification of their host red blood cells (RBCs) by preventing synthesis of new exported proteins, rather than by directly blocking the export of these proteins into the RBC compartment. Using in vitro models, we demonstrated that M5717 treated ring/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that in vivo persistence of M5717 treated iRBCs in the bloodstream is likely due to reduced cytoadherence and splenic clearance.
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Antimaláricos , Malaria Falciparum , Parásitos , Humanos , Animales , Ratones , Plasmodium falciparum , Eritrocitos/parasitología , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Bazo , Malaria Falciparum/parasitologíaRESUMEN
Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.
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Cefoxitina , Sepsis , Masculino , Adulto , Humanos , Anciano , Cefoxitina/uso terapéutico , Piperacilina/uso terapéutico , Pancreaticoduodenectomía/efectos adversos , Fístula Pancreática/tratamiento farmacológico , Ácido Penicilánico/uso terapéutico , Antibacterianos/uso terapéutico , Combinación Piperacilina y Tazobactam/uso terapéutico , Infección de la Herida Quirúrgica/prevención & control , Sepsis/tratamiento farmacológicoRESUMEN
OBJECTIVES: The lack of subnational mapping of the zoonotic cestode Taenia solium in endemic countries presents a major challenge to achieving intensified T. solium control milestones, as outlined in the "World Health Organization neglected tropical disease roadmap by 2030". We conducted a mapping study in Uganda, considered to be endemic, to identify subnational high-risk areas. METHODS: T. solium prevalence data, adjusted for diagnostic sensitivity and specificity in a Bayesian framework, were identified through a systematic review. Spatial autocorrelation and interpolation techniques were used to transform demographic and health survey cluster-level sanitation and poverty indicators, overlaid onto a pig density map for Uganda into modelled porcine cysticercosis (PCC) risk maps. RESULTS: A total of 16 articles (n = 11 PCC and n = 5 human cysticercosis (HCC) and/or human taeniasis) were included in the final analysis. The observed HCC prevalence ranged from 0.01% to 6.0% (confidence interval range: 0.004-11.4%), whereas the adjusted PCC ranged from 0.3 to 93.9% (uncertainty interval range: 0-99.8%). There was substantial variation in the modelled PCC risk factors and prevalence across Uganda and over time. CONCLUSION: The high PCC prevalence and moderate HCC exposure estimates indicate the need for urgent implementation of T. solium control efforts in Uganda.
Asunto(s)
Cisticercosis , Enfermedades de los Porcinos , Taenia solium , Teniasis , Animales , Humanos , Porcinos , Uganda/epidemiología , Teorema de Bayes , Enfermedades de los Porcinos/epidemiología , Cisticercosis/epidemiología , Teniasis/epidemiología , Factores de RiesgoRESUMEN
Transmission blocking interventions can stop malaria parasite transmission from mosquito to human by inhibiting parasite infection in mosquitos. One of the most advanced candidates for a malaria transmission blocking vaccine is Pfs230. Pfs230 is the largest member of the 6-cysteine protein family with 14 consecutive 6-cysteine domains and is expressed on the surface of gametocytes and gametes. Here, we present the crystal structure of the first two 6-cysteine domains of Pfs230. We identified high affinity Pfs230-specific nanobodies that recognized gametocytes and bind to distinct sites on Pfs230, which were isolated from immunized alpacas. Using two non-overlapping Pfs230 nanobodies, we show that these nanobodies significantly blocked P. falciparum transmission and reduced the formation of exflagellation centers. Crystal structures of the transmission blocking nanobodies with the first 6-cysteine domain of Pfs230 confirm that they bind to different epitopes. In addition, these nanobodies bind to Pfs230 in the absence of the prodomain, in contrast with the binding of known Pfs230 transmission blocking antibodies. These results provide additional structural insight into Pfs230 domains and elucidate a mechanism of action of transmission blocking Pfs230 nanobodies.