Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital ...warts (condyloma acuminata).Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up.Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world.Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy.Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6.Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied.Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma.Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up.Trial registrations NCT00092521 and NCT00092534.
The conference explored an extraordinary diversity of aging strategies in organisms ranging from short-lived species to "immortal" animals and plants. Research on the biological processes of aging is ...at the brink of a revolution with respect to our understanding of its underlying mechanisms as well as our ability to prevent and cure a wide variety of age-related pathologies.
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short ...stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP-related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection-the major risk factor for cervical cancer. Few reported ...prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women.
Data were obtained from HIV-infected and -uninfected female participants in the North American AIDS Cohort Collaboration on Research and Design with no history of ICC at enrollment. Participants were followed from study entry or January 1996 through ICC, loss to follow-up, or December 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios. All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction.
A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 person-years, respectively). HIV-infected women with baseline CD4+ T-cells of ≥350, 200-349, and <200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in ICC incidence, respectively, compared with HIV-uninfected women (P(trend) = 0.001). Of the 17 HIV-infected women, medical records for the 5 years before diagnosis showed that 6 had no documented screening, 5 had screening with low-grade or normal results, and 6 had high-grade results.
This study found elevated incidence of ICC in HIV-infected compared with -uninfected women, and these rates increased with immunosuppression.
The conference explored an extraordinary diversity of aging strategies in organisms ranging from short‐lived species to “immortal” animals and plants. Research on the biological processes of aging is ...at the brink of a revolution with respect to our understanding of its underlying mechanisms as well as our ability to prevent and cure a wide variety of age‐related pathologies.
Estimating the reproducibility of psychological science Aarts, Alexander A.; Nilsonne, Gustav; Zuni, Kellylynn
Science (American Association for the Advancement of Science),
08/2015, Letnik:
349, Številka:
6251
Journal Article
Recenzirano
Odprti dostop
Empirically analyzing empirical evidence
One of the central goals in any scientific endeavor is to understand causality. Experiments that seek to demonstrate a cause/effect relation most often ...manipulate the postulated causal factor. Aarts
et al.
describe the replication of 100 experiments reported in papers published in 2008 in three high-ranking psychology journals. Assessing whether the replication and the original experiment yielded the same result according to several criteria, they find that about one-third to one-half of the original findings were also observed in the replication study.
Science
, this issue
10.1126/science.aac4716
A large-scale assessment suggests that experimental reproducibility in psychology leaves a lot to be desired.
INTRODUCTION
Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. Scientific claims should not gain credence because of the status or authority of their originator but by the replicability of their supporting evidence. Even research of exemplary quality may have irreproducible empirical findings because of random or systematic error.
RATIONALE
There is concern about the rate and predictors of reproducibility, but limited evidence. Potentially problematic practices include selective reporting, selective analysis, and insufficient specification of the conditions necessary or sufficient to obtain the results. Direct replication is the attempt to recreate the conditions believed sufficient for obtaining a previously observed finding and is the means of establishing reproducibility of a finding with new data. We conducted a large-scale, collaborative effort to obtain an initial estimate of the reproducibility of psychological science.
RESULTS
We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. There is no single standard for evaluating replication success. Here, we evaluated reproducibility using significance and
P
values, effect sizes, subjective assessments of replication teams, and meta-analysis of effect sizes. The mean effect size (r) of the replication effects (
M
r
= 0.197, SD = 0.257) was half the magnitude of the mean effect size of the original effects (
M
r
= 0.403, SD = 0.188), representing a substantial decline. Ninety-seven percent of original studies had significant results (
P
< .05). Thirty-six percent of replications had significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
CONCLUSION
No single indicator sufficiently describes replication success, and the five indicators examined here are not the only ways to evaluate reproducibility. Nonetheless, collectively these results offer a clear conclusion: A large portion of replications produced weaker evidence for the original findings despite using materials provided by the original authors, review in advance for methodological fidelity, and high statistical power to detect the original effect sizes. Moreover, correlational evidence is consistent with the conclusion that variation in the strength of initial evidence (such as original
P
value) was more predictive of replication success than variation in the characteristics of the teams conducting the research (such as experience and expertise). The latter factors certainly can influence replication success, but they did not appear to do so here.
Reproducibility is not well understood because the incentives for individual scientists prioritize novelty over replication. Innovation is the engine of discovery and is vital for a productive, effective scientific enterprise. However, innovative ideas become old news fast. Journal reviewers and editors may dismiss a new test of a published idea as unoriginal. The claim that “we already know this” belies the uncertainty of scientific evidence. Innovation points out paths that are possible; replication points out paths that are likely; progress relies on both. Replication can increase certainty when findings are reproduced and promote innovation when they are not. This project provides accumulating evidence for many findings in psychological research and suggests that there is still more work to do to verify whether we know what we think we know.
Original study effect size versus replication effect size (correlation coefficients).
Diagonal line represents replication effect size equal to original effect size. Dotted line represents replication effect size of 0. Points below the dotted line were effects in the opposite direction of the original. Density plots are separated by significant (blue) and nonsignificant (red) effects.
Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
Patients with diabetes mellitus (DM) are at severely increased risk of developing atherosclerosis. Intraplaque neovascularization (IPN) and plaque ulceration are markers of the vulnerable plaque, ...which is at an increased risk of rupture and may lead to cardiovascular events. The aim of this study was to assess the prevalence of subclinical carotid atherosclerosis, intraplaque neovascularization (IPN), and plaque ulceration in asymptomatic patients with DM.
A total of 51 asymptomatic patients with DM underwent standard carotid ultrasound in conjunction with contrast-enhanced ultrasound (CEUS) to assess the prevalence of subclinical atherosclerosis, IPN, and plaque ulceration. Subclinical atherosclerosis was defined as the presence of atherosclerotic plaque, according to the Mannheim consensus. Semi-automated quantification software was used to assess IPN in suitable plaques. Plaque ulceration was defined as a disruption of the plaque-lumen border of ≥ 1 × 1 mm. A total of 408 carotid segments in 102 carotid arteries were investigated. Forty-six (90%) patients had subclinical atherosclerotic plaques, with a median plaque thickness of 2.4 mm (inter-quartile range 1.9-3.0). CEUS revealed IPN in 88% of the patients. In 10 carotid segments (8%), the plaque had an ulcerated surface. The presence of IPN could not be predicted by the presence of clinical characteristics including complications of DM (P > 0.05).
Patients with DM have a high prevalence (90%) of subclinical carotid atherosclerosis. Severe IPN and plaque ulceration, which are markers of the vulnerable plaque type, were detected in, respectively, 13 and 9% of these patients.
Abstract Obesity has become a major public health concern worldwide. Pharmacological interventions with the glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have shown promising results in ...facilitating weight loss and improving metabolic outcomes in individuals with obesity. Quantifying drug effects of GLP‐1RAs on energy intake (EI) and body weight (BW) using a QSP modeling approach can further increase the mechanistic understanding of these effects, and support obesity drug development. An extensive literature‐based dataset was created, including data from several diet, liraglutide and semaglutide studies and their effects on BW and related parameters. The Hall body composition model was used to quantify and predict effects on EI. The model was extended with (1) a lifestyle change/placebo effect on EI, (2) a weight loss effect on activity for the studies that included weight management support, and (3) a GLP‐1R agonistic effect using in vitro potency efficacy information. The estimated reduction in EI of clinically relevant dosages of semaglutide (2.4 mg) and liraglutide (3.0 mg) was 34.5% and 13.0%, respectively. The model adequately described the resulting change in BW over time. At 20 weeks the change in BW was estimated to be −17% for 2.4 mg semaglutide and −8% for 3 mg liraglutide, respectively. External validation showed the model was able to predict the effect of semaglutide on BW in the STEP 1 study. The GLP‐1RA body composition model can be used to quantify and predict the effect of novel GLP‐1R agonists on BW and changes in underlying processes using early in vitro efficacy information.
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under ...chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.
Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18-related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the ...efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18-related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% 95% confidence interval (95% CI), 93.3-99.8 and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18-related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.
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