The movement towards open science is a consequence of seemingly pervasive failures to replicate previous research. This transition comes with great benefits but also significant challenges that are ...likely to affect those who carry out the research, usually early career researchers (ECRs). Here, we describe key benefits, including reputational gains, increased chances of publication, and a broader increase in the reliability of research. The increased chances of publication are supported by exploratory analyses indicating null findings are substantially more likely to be published via open registered reports in comparison to more conventional methods. These benefits are balanced by challenges that we have encountered and that involve increased costs in terms of flexibility, time, and issues with the current incentive structure, all of which seem to affect ECRs acutely. Although there are major obstacles to the early adoption of open science, overall open science practices should benefit both the ECR and improve the quality of research. We review 3 benefits and 3 challenges and provide suggestions from the perspective of ECRs for moving towards open science practices, which we believe scientists and institutions at all levels would do well to consider.
Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO).
Prospective, randomized, sham ...injection-controlled, double-masked, multicenter trial.
A total of 397 patients with macular edema after BRVO.
Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met.
The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed.
Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified.
At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO.
Proprietary or commercial disclosure may be found after the references.
Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The ...lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles—the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation—with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.
The description of macrophage activation status is contentious and confusing. Murray et al. propose a framework for macrophage-activation nomenclature.
An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR ...expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD VIEW 1, VIEW 2) of neovascular age-related macular degeneration (AMD) compared monthly and ...every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab.
Double-masked, multicenter, parallel-group, active-controlled, randomized trials.
Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.
Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).
The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study ETDRS chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures.
All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.
Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.
Proprietary or commercial disclosure may be found after the references.
Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain ...undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular ...age-related macular degeneration (wet AMD).
A 24-month, phase III, randomized, multicenter, double-masked, dose-response study.
Patients aged ≥50 years with subfoveal wet AMD.
Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses.
The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data.
At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was −172.0 μm, −161.2 μm, −163.3 μm, and −172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups.
At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9–7.7) than the monthly groups (11.2–11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD.
Proprietary or commercial disclosure may be found after the references.
We synthesize insights from current understanding of drought impacts at stand‐to‐biogeographic scales, including management options, and we identify challenges to be addressed with new research. ...Large stand‐level shifts underway in western forests already are showing the importance of interactions involving drought, insects, and fire. Diebacks, changes in composition and structure, and shifting range limits are widely observed. In the eastern US, the effects of increasing drought are becoming better understood at the level of individual trees, but this knowledge cannot yet be confidently translated to predictions of changing structure and diversity of forest stands. While eastern forests have not experienced the types of changes seen in western forests in recent decades, they too are vulnerable to drought and could experience significant changes with increased severity, frequency, or duration in drought. Throughout the continental United States, the combination of projected large climate‐induced shifts in suitable habitat from modeling studies and limited potential for the rapid migration of tree populations suggests that changing tree and forest biogeography could substantially lag habitat shifts already underway. Forest management practices can partially ameliorate drought impacts through reductions in stand density, selection of drought‐tolerant species and genotypes, artificial regeneration, and the development of multistructured stands. However, silvicultural treatments also could exacerbate drought impacts unless implemented with careful attention to site and stand characteristics. Gaps in our understanding should motivate new research on the effects of interactions involving climate and other species at the stand scale and how interactions and multiple responses are represented in models. This assessment indicates that, without a stronger empirical basis for drought impacts at the stand scale, more complex models may provide limited guidance.
Social media has become a modern arena for human life, with billions of daily users worldwide. The intense popularity of social media is often attributed to a psychological need for social rewards ...(likes), portraying the online world as a Skinner Box for the modern human. Yet despite such portrayals, empirical evidence for social media engagement as reward-based behavior remains scant. Here, we apply a computational approach to directly test whether reward learning mechanisms contribute to social media behavior. We analyze over one million posts from over 4000 individuals on multiple social media platforms, using computational models based on reinforcement learning theory. Our results consistently show that human behavior on social media conforms qualitatively and quantitatively to the principles of reward learning. Specifically, social media users spaced their posts to maximize the average rate of accrued social rewards, in a manner subject to both the effort cost of posting and the opportunity cost of inaction. Results further reveal meaningful individual difference profiles in social reward learning on social media. Finally, an online experiment (n = 176), mimicking key aspects of social media, verifies that social rewards causally influence behavior as posited by our computational account. Together, these findings support a reward learning account of social media engagement and offer new insights into this emergent mode of modern human behavior.
Food preferences and dietary habits are heavily influenced by taste perception. There is growing interest in characterizing taste preferences based on genetic variation. Genetic differences in the ...ability to perceive key tastes may impact eating behavior and nutritional intake. Therefore, increased understanding of taste biology and genetics may lead to new personalized strategies, which may prevent or influence the trajectory of chronic disease risk. Recent advances show that single nucleotide polymorphisms (SNPs) in the CD36 fat taste receptor are linked to differences in fat perception, fat preference, and chronic-disease biomarkers. Genetic variation in the sweet taste receptor T1R2 has been shown to alter sweet taste preferences, eating behaviors, and risk of dental caries. Polymorphisms in the bitter taste receptor T2R38 have been shown to influence taste for brassica vegetables. Individuals that intensely taste the bitterness of brassica vegetables ("supertasters") may avoid vegetable consumption and compensate by increasing their consumption of sweet and fatty foods, which may increase risk for chronic disease. Emerging evidence also suggests that the role of genetics in taste perception may be more impactful in children due to the lack of cultural influence compared to adults. This review examines the current knowledge of SNPs in taste receptors associated with fat, sweet, bitter, umami, and salt taste modalities and their contributions to food preferences, and chronic disease. Overall, these SNPs demonstrate the potential to influence food preferences and consequently health.
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