Numbers needed to treat or harm and likelihood of being helped versus harmed for fremanezumab in patients who had prior inadequate response to two to four classes of migraine preventive medications: A post hoc analysis

Objective

This study aimed to determine the number needed to treat (NNT), number needed to harm (NNH), and likelihood of being helped or harmed (LHH) in a post hoc analysis of the phase 3b FOCUS trial.

Background

Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene–related peptide (CGRP), has demonstrated efficacy, tolerability, and safety in adults with episodic migraine (EM) or chronic migraine (CM), with documented previous inadequate response to two to four classes of migraine preventive medications.

Methods

In the 12-week double-blind period of the FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. NNT was based on responder analysis, defined as ≥50% reduction in monthly average number of migraine days at 12 weeks. NNH was based on discontinuations due to adverse events (AEs).

Results

Among patients with CM (n = 509), response rates and discontinuation rates were 27% (45/169) and 0 for quarterly fremanezumab, 29% (50/173) and 2% (3/173) for monthly fremanezumab, and 8% (13/167) and <1% (1/167) for placebo, respectively. These results translated to NNTs of 5.3 and 4.7, NNHs of 1000 and 88, and LHHs of 188 and 19 for quarterly and monthly fremanezumab, respectively. Among patients with EM (n = 328), response rates were 47% (50/107) for quarterly fremanezumab, 43% (47/110) for monthly fremanezumab, and 10% (11/111) for placebo. Discontinuation rates were <1% (n = 1) in all three groups. These results translated to NNTs of 2.7 and 3.0, NNHs of 1000 and 1000, and LHHs of 368 and 328 for quarterly and monthly fremanezumab, respectively.

Conclusions

The NNT, NNH, and LHH for quarterly and monthly fremanezumab compare favorably with those for traditional oral preventive medications, including topiramate, valproate, and propranolol.     

The developmental miRNA profiles of zebrafish as determined by small RNA cloning

MicroRNAs (miRNAs) represent a family of small, regulatory, noncoding RNAs that are found in plants and animals. Here, we describe the miRNA profile of the zebrafish Danio rerio resolved in a developmental and cell-type-specific manner. The profiles were obtained from larger-scale sequencing of small RNA libraries prepared from developmentally staged zebrafish, and two adult fibroblast cell lines derived from the caudal fin (ZFL) and the liver epithelium (SJD). We identified a total of 154 distinct miRNAs expressed from 343 miRNA genes. Other experimental/computational sources support an additional 10 miRNAs encoded by 19 genes. The miRNAs can be classified into 87 distinct families. Cross-species comparison indicates that 81 families are conserved in mammals, 17 of which also have at least one member conserved in an invertebrate. Our analysis reveals that the zygotes are essentially devoid of miRNAs and that their expression begins during the blastula period with a zebrafish-specific family of miRNAs encoded by closely spaced multicopy genes. Computational predictions of zebrafish miRNA targets are provided that take into account the depth of evolutionary conservation. Besides miRNAs, we identified a prominent class of repeat-associated small interfering RNAs (rasiRNAs).     

Superhydrophobic surfaces for extreme environmental conditions

Superhydrophobic surfaces for repelling impacting water droplets are typically created by designing structures with capillary (antiwetting) pressures greater than those of the incoming droplet (dynamic, water hammer). Recent work has focused on the evolution of the intervening air layer between droplet and substrate during impact, a balance of air compression and drainage within the surface texture, and its role in affecting impalement under ambient conditions through local changes in the droplet curvature. However, little consideration has been given to the influence of the intervening air-layer thermodynamic state and composition, in particular when departing from standard atmospheric conditions, on the antiwetting behavior of superhydrophobic surfaces. Here, we explore the related physics and determine the working envelope for maintaining robust superhydrophobicity, in terms of the ambient pressure and water vapor content. With single-tier and multitier superhydrophobic surfaces and high-resolution dynamic imaging of the droplet meniscus and its penetration behavior into the surface texture, we expose a trend of increasing impalement severity with decreasing ambient pressure and elucidate a previously unexplored condensation-based impalement mechanism within the texture resulting from the compression, and subsequent supersaturation, of the intervening gas layer in low-pressure, humid conditions. Using fluid dynamical considerations and nucleation thermodynamics, we provide mechanistic understanding of impalement and further employ this knowledge to rationally construct multitier surfaces with robust superhydrophobicity, extending water repellency behavior well beyond typical atmospheric conditions. Such a property is expected to find multifaceted use exemplified by transportation and infrastructure applications where exceptional repellency to water and ice is desired.

Inspired by nature, microtextured and nanotextured surfaces have demonstrated unique droplet repellent properties (1), which are beneficial for self-cleaning (2), antiicing (3), and condensation enhancement (4). For many practical applications, repelling an impacting water droplet is important. Much work has been performed to understand how surface topography and composition stabilize the Cassie–Baxter wetting state (5), a prerequisite for high droplet repellency, under static (6, 7) and dynamic (8–24) conditions to preclude transitioning to the Wenzel wetting state (25). To prevent the Cassie–Baxter to Wenzel wetting-state transition, hereafter defined as impalement, the capillary (antiwetting, surface property) pressure must exceed the wetting (droplet) pressure (9, 17). In previous research, the latter has been attributed to the dynamic pressure (17), effective water hammer (10, 11, 16, 23), and deformation of the droplet by the compressed air layer leading to a ring-shaped pressure maximum (13, 26).It is established that the use of hierarchical surface texture and low-surface energy coatings are key components for achieving liquid repellency and preventing impalement (13, 15, 16, 27). Much of this understanding is based on work conducted under ambient conditions; however, work on droplet mobility that departs from ambient environmental conditions (28–31) [i.e., substrate cooling (13, 32), supercooled droplet impact (33, 34), ambient pressure reduction (35–37), and droplet heating (38)] is yielding new insight into, and unveils new requirements for, the rational design of superrepellent surfaces. Mechanisms for the loss of superrepellent behavior include condensation-based impalement in the presence of hot vapor (warm droplets) (28, 38), increased droplet viscosity (33), and rapid recalescent freezing inhibiting droplet recoil (cold droplets) (32, 34). Therefore, in addition to wettability, it is necessary to investigate important aspects such as nonstandard atmosphere environments and nucleation (3, 39, 40)—which affect the intervening gas-layer dynamic state during droplet impact and enhance droplet–substrate adhesion—to enable surface texture tailoring to counter such effects to preserve superhydrophobicity (38, 41–46). While the effects of droplet and environmental temperature (hot or cold) on superhydrophobicity for impacting droplets are being better understood, research into the effect of the environmental gas pressure, an equally important counterpart, is comparatively scant (35–37), as is the combined effect with humidity. Both are very important for defining the thermodynamic state of the intervening gas layer during droplet impact, necessary to determine its behavior. Previous work has demonstrated that decreasing the environmental pressure influences the droplet impact dynamics on smooth and rough surfaces (e.g., prompt vs. thin-sheet splashing) (26, 47–50), which may alter impact and recoil dynamics on superhydrophobic surfaces; however, this remains to be seen.Here, we examine, experimentally and theoretically, the combined effects of reducing environmental pressure and varying humidity on droplet impact and recoil from superhydrophobic surfaces, identify impalement mechanisms, and armed with this knowledge, rationally nanoengineer robust superhydrophobic surfaces that can repel impacting droplets across a wide range of environmental conditions. We demonstrate that the likelihood of impalement on textured surfaces increases as the ambient pressure decreases and provide rationales to explain this. Additionally, through variation of the relative humidity, we report, and theoretically underpin, a hitherto unknown mechanism for wetting-state transition through supersaturation of, and subsequent condensation within, the air layer resulting from the pressure increase beneath an impacting droplet. Finally, we demonstrate an alternative coating capable of resisting impalement within the working envelope experimentally explored, based on our accrued knowledge. We believe that our observations will have profound implications for all applications of superhydrophobicity in both low-pressure, such as those involving ice accretion on aircraft through superior repellency of supercooled drops, and naturally humid environments, including for self-cleaning materials such as textiles.     

Characteristics of high‐ and low‐risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes

Aim

To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273.

Methods

We conducted a prospective, randomized, double‐blind, placebo‐controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high‐ or low‐risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis.

Results

A total of 1777 participants from 15 centres were included, with 12.3% of these having a high‐risk proteomic pattern. Participants in the high‐risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low‐risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R² < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin‐angiotensin system‐blocking agents remained significant determinants of the CKD273 high‐risk group: area under the curve 0.72 (95% CI 0.68–0.75; P<0.01).

Conclusions

In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012‐000452‐34 and Clinicaltrials.gov: NCT02040441).