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"Kaplan, M"
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Influence of a COVID-19 vaccine’s effectiveness and safety profile on vaccination acceptance
Although a safe and effective vaccine holds the greatest promise for resolving the COVID-19 pandemic, hesitancy to accept vaccines remains common. To explore vaccine acceptance decisions, we conducted a national survey of 1,000 people from all US states in August of 2020 and a replication in December of 2020. Using a 3 × 3 × 3 factorial experimental design, we estimated the impact of three factors: probability of 1) protection against COVID-19, 2) minor side effects, and 3) a serious adverse reactions. The outcome was respondents’ reported likelihood of receiving a vaccine for the coronavirus. Probability of vaccine efficacy (50%, 70%, or 90%) had the largest effect among the three factors. The probability of minor side effects (50%, 75%, 90%) including fever and sore arm, did not significantly influence likelihood of receiving the vaccine. The chances of a serious adverse reaction, such as temporary or permanent paralysis, had a small but significant effect. A serious adverse reaction rate of 1/100,000 was more likely to discourage vaccine use in comparison to rates of 1/million or 1/100 million. All interactions between the factors were nonsignificant. A replication following the announcement that vaccines were 95% effective showed small, but significant increases in the likelihood of taking a vaccine. The main effects and interactions in the model remained unchanged. Expected benefit was more influential in respondents’ decision making than expected side effects. The absence of interaction effects suggests that respondents consider the side effects and benefits independently.
Journal Article
Beyond cybersecurity : protecting your digital business
\"The book's content is based on McKinsey's proprietary research, client experience and interviews with over 200 executives, regulators and security experts. This effort has four main findings: Pervasive digitization, open and inter-connected technology environments and sophisticated attackers make cyber-attacks a critical social and business issue that could materially slow the pace of technology and bushiness innovation with as much as $3 trillion in aggregate impact. There's a high degree of consensus among enterprise technology executives about the nature of a step-change capability improvement required to make their institutions cyber-resilient. While institutions need to start acting to improve their capabilities now, there should be enhanced collaboration across the cyber-security ecosystem to get alignment on a broad range of policy issues. Progress toward cyber-resiliency can only be achieved with active engagement from the most senior business and public leaders\"--Publisher's description.
Book
Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known.
We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.
We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.
In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).
Journal Article
Likelihood of Null Effects of Large NHLBI Clinical Trials Has Increased over Time
We explore whether the number of null results in large National Heart Lung, and Blood Institute (NHLBI) funded trials has increased over time.
We identified all large NHLBI supported RCTs between 1970 and 2012 evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease. Trials were included if direct costs >$500,000/year, participants were adult humans, and the primary outcome was cardiovascular risk, disease or death. The 55 trials meeting these criteria were coded for whether they were published prior to or after the year 2000, whether they registered in clinicaltrials.gov prior to publication, used active or placebo comparator, and whether or not the trial had industry co-sponsorship. We tabulated whether the study reported a positive, negative, or null result on the primary outcome variable and for total mortality.
17 of 30 studies (57%) published prior to 2000 showed a significant benefit of intervention on the primary outcome in comparison to only 2 among the 25 (8%) trials published after 2000 (χ2=12.2,df= 1, p=0.0005). There has been no change in the proportion of trials that compared treatment to placebo versus active comparator. Industry co-sponsorship was unrelated to the probability of reporting a significant benefit. Pre-registration in clinical trials.gov was strongly associated with the trend toward null findings.
The number NHLBI trials reporting positive results declined after the year 2000. Prospective declaration of outcomes in RCTs, and the adoption of transparent reporting standards, as required by clinicaltrials.gov, may have contributed to the trend toward null findings.
Journal Article
Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults
In 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials.
Secondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults (NCT04368728 and NCT04470427), focusing analysis on Brighton Collaboration adverse events of special interest.
Pfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI −0.4 to 20.6 and −3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI –23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI −3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39).
The excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.
Journal Article
More than medicine : the broken promise of American health
American science produces the best--and most expensive--medical treatments in the world. Yet U.S. citizens lag behind their global peers in life expectancy and quality of life. Robert Kaplan brings together extensive data to make the case that health care priorities in the United States are sorely misplaced. America's medical system is invested in attacking disease, but not in addressing the social, behavioral, and environmental problems that engender disease in the first place. Medicine is important, but many Americans act as though it were all important. The U.S. stakes much of its health funding on the promise of high-tech diagnostics and miracle treatments, while ignoring strong evidence that many of the most significant pathways to health are nonmedical. Americans spend millions on drugs to treat high cholesterol, for example, which increase life expectancy by six to eight months on average. But they underfund education, which might extend life expectancy by as much as twelve years. Wars on infectious disease have paid off, but clinical trials for chronic conditions--costing billions--rarely confirm that new treatments extend life. By comparison, the National Institutes of Health spends just 3 percent of its budget on research in social and behavioral determinants of health, even though these factors account for 50 percent of premature deaths. America's failure to take prevention seriously costs lives. More than Medicine argues that we need a shake-up in how we invest resources, and it offers a bold new vision for longer, healthier living.-- Provided by publisher
Book
Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation
Ancylostoma caninum is an important zoonotic gastrointestinal nematode of dogs worldwide and a close relative of human hookworms. We recently reported that racing greyhound dogs in the USA are infected with A . caninum that are commonly resistant to multiple anthelmintics. Benzimidazole resistance in A . caninum in greyhounds was associated with a high frequency of the canonical F167Y(T T C>T A C) isotype-1 β-tubulin mutation. In this work, we show that benzimidazole resistance is remarkably widespread in A . caninum from domestic dogs across the USA. First, we identified and showed the functional significance of a novel benzimidazole isotype-1 β-tubulin resistance mutation, Q134H(CA A >CA T ). Several benzimidazole resistant A . caninum isolates from greyhounds with a low frequency of the F167Y(T T C>T A C) mutation had a high frequency of a Q134H(CA A >CA T ) mutation not previously reported from any eukaryotic pathogen in the field. Structural modeling predicted that the Q134 residue is directly involved in benzimidazole drug binding and that the 134H substitution would significantly reduce binding affinity. Introduction of the Q134H substitution into the C . elegans β-tubulin gene ben-1 , by CRISPR-Cas9 editing, conferred similar levels of resistance as a ben-1 null allele. Deep amplicon sequencing on A . caninum eggs from 685 hookworm positive pet dog fecal samples revealed that both mutations were widespread across the USA, with prevalences of 49.7% (overall mean frequency 54.0%) and 31.1% (overall mean frequency 16.4%) for F167Y(T T C>T A C) and Q134H(CA A >CA T ), respectively. Canonical codon 198 and 200 benzimidazole resistance mutations were absent. The F167Y(T T C>T A C) mutation had a significantly higher prevalence and frequency in Western USA than in other regions, which we hypothesize is due to differences in refugia. This work has important implications for companion animal parasite control and the potential emergence of drug resistance in human hookworms.
Journal Article