Abstracts in high profile journals often fail to report harm

<p>Abstract</p> <p>Background</p> <p>To describe how frequently harm is reported in the abstract of high impact factor medical journals.</p> <p>Methods</p> <p><it>Design and population</it>: We carried out a blinded structured review of a random sample of 363 Randomised Controlled Trials (RCTs) carried out on human beings, and published in high impact factor medical journals in 2003. <it>Main endpoint</it>: 1) Proportion of articles reporting harm in the abstract; and 2) Proportion of articles that reported harm in the abstract when harm was reported in the main body of the article. <it>Analysis</it>: Corrected Prevalence Ratio (cPR) and its exact confidence interval were calculated. Non-conditional logistic regression was used.</p> <p>Results</p> <p>363 articles and 407 possible comparisons were studied. Overall, harm was reported in 135 abstracts [37.2% (CI95%:32.2 to 42.4)]. Harm was reported in the main text of 243 articles [66.9% (CI95%: 61.8 to 71.8)] and was statistically significant in 54 articles [14.9% (CI95%: 11.4 to 19.0)]. Among the 243 articles that mentioned harm in the text, 130 articles [53.5% (CI95% 47.0 to 59.9)] reported harm in the abstract; a figure that rose to 75.9% (CI95%: 62.4 to 86.5) when the harm reported in the text was statistically significant. Harm in the abstract was more likely to be reported when statistically significant harm was reported in the main body of the article [cPR = 1.70 (CI95% 1.47 to 1.92)] and when drug companies (not public institutions) funded the RCTs [cPR = 1.29 (CI95% 1.03 to 1.67)].</p> <p>Conclusion</p> <p>Abstracts published in high impact factor medical journals underreport harm, even when harm is reported in the main body of the article.</p

Can postponement of an adverse outcome be used to present risk reductions to a lay audience? A population survey

BACKGROUND: For shared decision making doctors need to communicate the effectiveness of therapies such that patients can understand it and discriminate between small and large effects. Previous research indicates that patients have difficulties in understanding risk measures. This study aimed to test the hypothesis that lay people may be able to discriminate between therapies when their effectiveness is expressed in terms of postponement of an adverse disease event. METHODS: In 2004 a random sample of 1,367 non-institutionalized Danes aged 40+ was interviewed in person. The participants were asked for demographic information and asked to consider a hypothetical preventive drug treatment. The respondents were randomized to the magnitude of treatment effectiveness (heart attack postponement of 1 month, 6 months, 12 months, 2 years, 4 years and 8 years) and subsequently asked whether they would take such a therapy. They were also asked whether they had hypercholesterolemia or had experienced a heart attack. RESULTS: In total 58% of the respondents consented to the hypothetical treatment. The proportions accepting treatment were 39%, 52%, 56%, 64%, 67% and 73% when postponement was 1 month, 6 months, 12 months, 2 years, 4 years and 8 years respectively. Participants who thought that the effectiveness information was difficult to understand, were less likely to consent to therapy (p = 0.004). CONCLUSION: Lay people can discriminate between levels of treatment effectiveness when they are presented in terms of postponement of an adverse event. The results indicate that such postponement is a comprehensible measure of effectiveness

Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of Kras G12D;Pik3ca H1047R or Trp53 R172H and/or ablation of Pten or Trp53. We find that Kras G12D;Pik3ca H1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer. </p

Educating public health physicians for the future: a current perspective from Aotearoa New Zealand

Persisting, and in some cases widening, inequalities in health within and between countries present significant challenges to the focus and practice of contemporary public health, and by association, to public health education. As public health physicians and academic educators of medically- and non-medically trained public health practitioners, we call for a radical re-think of current approaches to public health medicine education and training in order to address these challenges. The public health physicians of the future, we argue, require not merely technical knowledge and skills but also a set of values that underpin a commitment to ethical principles, social equity, human rights, compassionate action, advocacy and leadership. Furthermore, while they will need to have their action firmly grounded in local realities they should think, if not speak and act, from an informed awareness of global issues. Drawing from our experience in Aotearoa New Zealand, as well as with marginalised communities overseas, we proffer our suggestions for the process and content of public health physician education and training for the future, with the intention of stimulating debate

Laypersons' understanding of relative risk reductions: Randomised cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Despite increasing recognition of the importance of involving patients in decisions on preventive healthcare interventions, little is known about how well patients understand and utilise information provided on the relative benefits from these interventions. The aim of this study was to explore whether lay people can discriminate between preventive interventions when effectiveness is presented in terms of relative risk reduction (RRR), and whether such discrimination is influenced by presentation of baseline risk.</p> <p>Methods</p> <p>The study was a randomised cross-sectional interview survey of a representative sample (n = 1,519) of lay people with mean age 59 (range 40–98) years in Denmark. In addition to demographic information, respondents were asked to consider a hypothetical drug treatment to prevent heart attack. Its effectiveness was randomly presented as RRR of 10, 20, 30, 40, 50 or 60 percent, and half of the respondents were presented with quantitative information on the baseline risk of heart attack. The respondents had also been asked whether they were diagnosed with hypercholesterolemia or had experienced a heart attack.</p> <p>Results</p> <p>In total, 873 (58%) of the respondents consented to the hypothetical treatment. While 49% accepted the treatment when RRR = 10%, the acceptance rate was 58–60% for RRR>10. There was no significant difference in acceptance rates across respondents irrespective of whether they had been presented with quantitative information on baseline risk or not.</p> <p>Conclusion</p> <p>In this study, lay people's decisions about therapy were only slightly influenced by the magnitude of the effect when it was presented in terms of RRR. The results may indicate that lay people have difficulties in discriminating between levels of effectiveness when they are presented in terms of RRR.</p

Identifying patient preferences for communicating risk estimates: A descriptive pilot study

BACKGROUND: Patients increasingly seek more active involvement in health care decisions, but little is known about how to communicate complex risk information to patients. The objective of this study was to elicit patient preferences for the presentation and framing of complex risk information. METHOD: To accomplish this, eight focus group discussions and 15 one-on-one interviews were conducted, where women were presented with risk data in a variety of different graphical formats, metrics, and time horizons. Risk data were based on a hypothetical woman's risk for coronary heart disease, hip fracture, and breast cancer, with and without hormone replacement therapy. Participants' preferences were assessed using likert scales, ranking, and abstractions of focus group discussions. RESULTS: Forty peri- and postmenopausal women were recruited through hospital fliers (n = 25) and a community health fair (n = 15). Mean age was 51 years, 50% were non-Caucasian, and all had completed high school. Bar graphs were preferred by 83% of participants over line graphs, thermometer graphs, 100 representative faces, and survival curves. Lifetime risk estimates were preferred over 10 or 20-year horizons, and absolute risks were preferred over relative risks and number needed to treat. CONCLUSION: Although there are many different formats for presenting and framing risk information, simple bar charts depicting absolute lifetime risk were rated and ranked highest overall for patient preferences for format

Multivariable risk prediction can greatly enhance the statistical power of clinical trial subgroup analysis

BACKGROUND: When subgroup analyses of a positive clinical trial are unrevealing, such findings are commonly used to argue that the treatment's benefits apply to the entire study population; however, such analyses are often limited by poor statistical power. Multivariable risk-stratified analysis has been proposed as an important advance in investigating heterogeneity in treatment benefits, yet no one has conducted a systematic statistical examination of circumstances influencing the relative merits of this approach vs. conventional subgroup analysis. METHODS: Using simulated clinical trials in which the probability of outcomes in individual patients was stochastically determined by the presence of risk factors and the effects of treatment, we examined the relative merits of a conventional vs. a "risk-stratified" subgroup analysis under a variety of circumstances in which there is a small amount of uniformly distributed treatment-related harm. The statistical power to detect treatment-effect heterogeneity was calculated for risk-stratified and conventional subgroup analysis while varying: 1) the number, prevalence and odds ratios of individual risk factors for risk in the absence of treatment, 2) the predictiveness of the multivariable risk model (including the accuracy of its weights), 3) the degree of treatment-related harm, and 5) the average untreated risk of the study population. RESULTS: Conventional subgroup analysis (in which single patient attributes are evaluated "one-at-a-time") had at best moderate statistical power (30% to 45%) to detect variation in a treatment's net relative risk reduction resulting from treatment-related harm, even under optimal circumstances (overall statistical power of the study was good and treatment-effect heterogeneity was evaluated across a major risk factor [OR = 3]). In some instances a multi-variable risk-stratified approach also had low to moderate statistical power (especially when the multivariable risk prediction tool had low discrimination). However, a multivariable risk-stratified approach can have excellent statistical power to detect heterogeneity in net treatment benefit under a wide variety of circumstances, instances under which conventional subgroup analysis has poor statistical power. CONCLUSION: These results suggest that under many likely scenarios, a multivariable risk-stratified approach will have substantially greater statistical power than conventional subgroup analysis for detecting heterogeneity in treatment benefits and safety related to previously unidentified treatment-related harm. Subgroup analyses must always be well-justified and interpreted with care, and conventional subgroup analyses can be useful under some circumstances; however, clinical trial reporting should include a multivariable risk-stratified analysis when an adequate externally-developed risk prediction tool is available

Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance

A torque-based method demonstrates increased rigidity in Parkinson’s disease during low-frequency stimulation

Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson’s disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson’s disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist

Health and Human Rights Education in U.S. Schools of Medicine and Public Health: Current Status and Future Challenges

BACKGROUND: Despite increasing recognition of the importance of human rights in the protection and promotion of health, formal human rights education has been lacking in schools of medicine and public health. Our objectives were: 1) to determine the nature and extent of health and human rights (HHR) education among schools of medicine (SOMs) and public health (SPHs); 2) to identify perceived barriers to implementing HHR curricula; 3) to learn about deans' interests and attitudes toward HHR education, and; 4) to identify factors associated with offering HHR education. METHODS AND PRINCIPAL FINDINGS: We conducted a cross-sectional survey among deans of all accredited allopathic SOMs and SPHs in the United States and Puerto Rico. Seventy-one percent of U.S. SOMs and SPHs responded. Thirty-seven percent of respondents indicated that their schools offered some form of HHR education. Main barriers to offering HHR education included competition for time, lack of qualified instructors and lack of funding. Among schools not offering HHR education, 35% of deans were interested in offering HHR education. Seventy-six percent of all deans believed that it was very important or important to offer HHR education. Multiple regression analysis revealed that deans' attitudes were the most important factor associated with offering any HHR education. CONCLUSION: Findings indicate that though a majority of deans of SOMs and SPHs believe that knowledge about human rights is important in health practice and support the inclusion of HHR studies in their schools, HHR education is lacking at most of their institutions. These results and the growing recognition of the critical interdependence between health and human rights indicate a need for SOMs and SPHs to work towards formal inclusion of HHR studies in their curricula, and that HHR competency requirements be considered to overcome barriers to its inclusion