Project description:Deaths from Plasmodium knowlesi malaria have been linked to delayed parenteral treatment. In Malaysia, early intravenous artesunate is now recommended for all severe malaria cases. We describe P. knowlesi fatalities in Sabah, Malaysia, during 2012-2014 and report species-specific fatality rates based on 2010-2014 case notifications. Sixteen malaria-associated deaths (caused by PCR-confirmed P. knowlesi [7], P. falciparum [7], and P. vivax [1] and microscopy-diagnosed "P. malariae" [1]) were reported during 2012-2014. Six patients with severe P. knowlesi malaria received intravenous artesunate at hospital admission. For persons ≥15 years of age, overall fatality rates during 2010-2014 were 3.4, 4.2, and 1.0 deaths/1,000 P. knowlesi, P. falciparum, and P. vivax notifications, respectively; P. knowlesi-associated fatality rates fell from 9.2 to 1.6 deaths/1,000 notifications. No P. knowlesi-associated deaths occurred among children, despite 373 notified cases. Although P. knowlesi malaria incidence is rising, the notification-fatality rate has decreased, likely due to improved use of intravenous artesunate.
Project description:Although exosomes were previously recognized as a mechanism for discharging useless cellular components, growing evidence has elucidated their roles in conveying information between cells. They contribute to cell-cell communication by carrying nucleic acids, proteins and lipids that can, in turn, regulate behavior of the target cells. Recent research suggested that exosomes extensively participate in progression of diverse cardiovascular diseases (CVDs), such as myocardial infarction, cardiomyopathy, pulmonary arterial hypertension and others. Here, we summarize effects of exosome-derived molecules (mainly microRNAs and proteins) on cardiac function, to examine their potential applications as biomarkers or therapeutics in CVDs.
Project description:We advanced a promising experimental vaccine for immunizing against the Lassa virus surface glycoprotein as a candidate for human trials. Preclinical evaluation of the vaccine candidate based on a live vesicular stomatitis virus (VSV) vector showed that it was highly efficacious in cynomolgus macaques consistent with earlier research studies, and that the animals developed serum antibodies that could mediate antiviral effector functions including direct neutralization of virus infectivity. As part of this evaluation, we analyzed whole-blood transcriptomes from each study subject prior to vaccination and at 1 day and 3 days post-vaccination.
Project description:The past few years have witnessed many promising advances in HIV prevention strategies involving preexposure prophylaxis approaches. Some may now wonder whether an HIV vaccine is still needed, and whether developing one is even possible. The partial efficacy reported in the RV144 trial and the encouraging results of the accompanying immune correlates analysis suggest that an effective HIV vaccine is achievable. These successes have provided a large impetus and guidance for conducting more HIV vaccine trials. A key lesson learned from RV144 is that assessment of HIV acquisition is now a feasible and valuable primary objective for HIV preventive vaccine trials. In this article we review how RV144 and other HIV vaccine efficacy trials have instructed the field and highlight some of the HIV vaccine concepts in clinical development. After a long and significant investment, HIV vaccine clinical research is paying off in the form of valuable lessons that, if applied effectively, will accelerate the path toward a safe and effective vaccine. Together with other HIV prevention approaches, preventive and therapeutic HIV vaccines will be invaluable tools in bringing the epidemic to an end.
Project description:BackgroundPhase III trials have estimated coronavirus disease 2019 (COVID-19) vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections.MethodsWe developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus, and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic, and any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections.ResultsVE against asymptomatic infection measured by polymerase chain reaction (PCR) or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias toward underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4-77.1) and 70.9% (95% UI 49.8-80.7), respectively.ConclusionsMultiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.
Project description:For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.
Project description:Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.
Project description:BackgroundVaccine regulatory decision making is based on vaccine efficacy against etiologically confirmed outcomes, which may underestimate the preventable disease burden. To quantify this underestimation, we compared vaccine-preventable disease incidence (VPDI) of clinically defined outcomes with radiologically/etiologically confirmed outcomes.MethodsWe performed a systematic review of efficacy trials for several vaccines (1997-2019) and report results for pneumococcal conjugate vaccines. Data were extracted for outcomes within a clinical syndrome, organized from most sensitive to most specific. VPDI was determined for each outcome, and VPDI ratios were calculated, with a clinically defined outcome (numerator) and a radiologically/etiologically confirmed outcome (denominator).ResultsAmong 9 studies, we calculated 27 VPDI ratios; 24 had a value >1. Among children, VPDI ratios for clinically defined versus vaccine serotype otitis media were 0.6 (95% CI not calculable), 2.1 (1.5-3.0), and 3.7 (1.0-10.2); the VPDI ratios comparing clinically defined with radiologically confirmed pneumonia ranged from not calculable to 2.7 (1.2-10.4); the VPDI ratio comparing clinically suspected invasive pneumococcal disease (IPD) with laboratory-confirmed IPD was 3.8 (95% CI not calculable). Among adults, the ratio comparing clinically defined with radiologically confirmed pneumonia was 1.9 (-6.0 to 9.1) and with vaccine serotype-confirmed pneumonia was 2.9 (.5-7.8).ConclusionsWhile there is substantial uncertainty around individual point estimates, there is a consistent trend in VPDI ratios, most commonly showing under-ascertainment of 1.5- to 4-fold, indicating that use of clinically defined outcomes is likely to provide a more accurate estimate of a pneumococcal conjugate vaccine's public health value.
Project description:The global burden of osteoporotic fractures is associated with significant morbidity, mortality, and healthcare costs. We examined the ClinicalTrials.gov database to determine whether recently registered clinical trials addressed prevention and treatment in those at high risk for fracture. A dataset of 96,346 trials registered in ClinicalTrials.gov was downloaded on September 27, 2010. At the time of the dataset download, 40,970 interventional trials had been registered since October 1, 2007. The osteoporosis subset comprised 239 interventional trials (0.6%). Those trials evaluating orthopedic procedures were excluded. The primary purpose was treatment in 67.0%, prevention in 20.1%, supportive care in 5.8%, diagnostic in 2.2%, basic science in 3.1%, health services research in 0.9%, and screening in 0.9%. The majority of studies (61.1%) included drug-related interventions. Most trials (56.9%) enrolled only women, 38.9% of trials were open to both men and women, and 4.2% enrolled only men. Roughly one fifth (19.7%) of trials excluded research participants older than 65 years, and 33.5% of trials excluded those older than 75 years. The funding sources were industry in 51.0%, the National Institutes of Health in 6.3%, and other in 42.7%. We found that most osteoporosis-related trials registered from October 2007 through September 2010 examined the efficacy and safety of drug treatment, and fewer trials examined prevention and non-drug interventions. Trials of interventions that are not required to be registered in ClinicalTrials.gov may be underrepresented. Few trials are specifically studying osteoporosis in men and older adults. Recently registered osteoporosis trials may not sufficiently address fracture prevention.
Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular malignant tumor with indolent course. Liver transplantation for local disease is the treatment of choice. In the metastatic setting there is no consensus regarding the appropriate systemic treatment. We present two cases of metastatic hepatic epithelioid hemangioendothelioma (hEHE) treated with the combination of Doxorubicin and Olaratumab. Both patients showed Stable Disease (SD) as a response, after the completion of six cycles of this combination therapy.