Evaluation of person-level heterogeneity of treatment effects in published multiperson N-of-1 studies: systematic review and reanalysis.

OBJECTIVE:Individual patients with the same condition may respond differently to similar treatments. Our aim is to summarise the reporting of person-level heterogeneity of treatment effects (HTE) in multiperson N-of-1 studies and to examine the evidence for person-level HTE through reanalysis. STUDY DESIGN:Systematic review and reanalysis of multiperson N-of-1 studies. DATA SOURCES:Medline, Cochrane Controlled Trials, EMBASE, Web of Science and review of references through August 2017 for N-of-1 studies published in English. STUDY SELECTION:N-of-1 studies of pharmacological interventions with at least two subjects. DATA SYNTHESIS:Citation screening and data extractions were performed in duplicate. We performed statistical reanalysis testing for person-level HTE on all studies presenting person-level data. RESULTS:We identified 62 multiperson N-of-1 studies with at least two subjects. Statistical tests examining HTE were described in only 13 (21%), of which only two (3%) tested person-level HTE. Only 25 studies (40%) provided person-level data sufficient to reanalyse person-level HTE. Reanalysis using a fixed effect linear model identified statistically significant person-level HTE in 8 of the 13 studies (62%) reporting person-level treatment effects and in 8 of the 14 studies (57%) reporting person-level outcomes. CONCLUSIONS:Our analysis suggests that person-level HTE is common and often substantial. Reviewed studies had incomplete information on person-level treatment effects and their variation. Improved assessment and reporting of person-level treatment effects in multiperson N-of-1 studies are needed

Reduced skin permeation and penetration of clobetasol propionate when Dermovate cream is applied at short time intervals with emollients

© 2023 The Authors. JEADV Clinical Practice published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. This is an open access article under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/Background: Dermovate cream containing 0.05% clobetasol propionate is a very potent topical corticosteroid (TCS) used in the treatment of severe inflammatory dermatoses. Regular emollient therapy should continue alongside clobetasol propionate treatment, however, the impact on drug delivery to the skin when both products are applied at similar times is unknown. Objectives: To assess whether application of emollients at similar times to Dermovate cream alter the delivery of clobetasol propionate to the skin. Methods: This study was conducted using ex vivo human skin mounted in Franz cells. Dermovate cream was applied before or after three different emollients, Hydromol Intensive cream, Doublebase gel, and Diprobase ointment at 5‐ or 30‐min intervals. Drug delivery to the skin was assessed up to 24 h using high‐performance liquid chromatography. Results: Significantly reduced clobetasol propionate delivery to the skin was observed when Dermovate cream was applied either before or after the three different emollients, compared to the application of Dermovate cream alone. The data suggest in situ formation of a mixed Dermovate cream and emollient layer which reduces clobetasol propionate delivery relative to the original product. Applying Dermovate cream after any emollient generally resulted in larger reductions in drug delivery to the skin, compared to when the steroid was applied first. This was attributed to the emollients forming an additional barrier to drug delivery at the skin‐formulation interface. Conclusions: These findings indicate that applying Dermovate cream at similar times as emollients can significantly reduce drug delivery to the skin and that separating the application of the two products by intervals of up to 30 min is not sufficient to mitigate this effect.Peer reviewe

Identifying the sources of uncertainty in climate model simulations of solar radiation modification with the G6sulfur and G6solar Geoengineering Model Intercomparison Project (GeoMIP) simulations

We present here results from the Geoengineering Model Intercomparison Project (GeoMIP) simulations for the experiments G6sulfur and G6solar for six Earth system models participating in the Climate Model Intercomparison Project (CMIP) Phase 6. The aim of the experiments is to reduce the warming that results from a high-tier emission scenario (Shared Socioeconomic Pathways SSP5-8.5) to that resulting from a medium-tier emission scenario (SSP2-4.5). These simulations aim to analyze the response of climate models to a reduction in incoming surface radiation as a means to reduce global surface temperatures, and they do so either by simulating a stratospheric sulfate aerosol layer or, in a more idealized way, through a uniform reduction in the solar constant in the model. We find that over the final two decades of this century there are considerable inter-model spreads in the needed injection amounts of sulfate (29±9Tg-SO2/yr between 2081 and 2100), in the latitudinal distribution of the aerosol cloud and in the stratospheric temperature changes resulting from the added aerosol layer. Even in the simpler G6solar experiment, there is a spread in the needed solar dimming to achieve the same global temperature target (1.91±0.44). The analyzed models already show significant differences in the response to the increasing CO2 concentrations for global mean temperatures and global mean precipitation (2.05K±0.42K and 2.28±0.80, respectively, for SSP5-8.5 minus SSP2-4.5 averaged over 2081-2100). With aerosol injection, the differences in how the aerosols spread further change some of the underlying uncertainties, such as the global mean precipitation response (-3.79±0.76 for G6sulfur compared to -2.07±0.40 for G6solar against SSP2-4.5 between 2081 and 2100). These differences in the behavior of the aerosols also result in a larger uncertainty in the regional surface temperature response among models in the case of the G6sulfur simulations, suggesting the need to devise various, more specific experiments to single out and resolve particular sources of uncertainty. The spread in the modeled response suggests that a degree of caution is necessary when using these results for assessing specific impacts of geoengineering in various aspects of the Earth system. However, all models agree that compared to a scenario with unmitigated warming, stratospheric aerosol geoengineering has the potential to both globally and locally reduce the increase in surface temperatures. © 2021 Daniele Visioni et al

Patient Characteristics Associated with Making Requests during Primary Care Visits

BackgroundPatient requests for tests, treatments, or referrals occur frequently during primary care visits and pose challenges for clinicians to address, but little is known about patient characteristics that may predict requests.ObjectiveTo identify patient characteristics associated with a higher rate of patient requests during primary care visits.Design, setting, and sampleCross-sectional analyses of data from 1141 adult patients attending 1319 visits with 56 primary care physicians (including 45 resident and 11 faculty physicians) in an academic family medicine practice.MeasurementsPostvisit patient surveys including measures of patient requests for tests, prescriptions, and referrals; sociodemographics; mental and physical health status; symptom bother or worry (3-item scale; range, 3 to 15; Cronbach's α = 0.83); global life satisfaction; medical skepticism; and Five Factor Model personality traits.ResultsPatients made 1 or more requests in 867 visits (65.7%). In multivariate analyses of the within-visit request count, the following patient variables were statistically significantly associated with a higher rate of requests: age in years (incidence rate ratio [IRR], 1.01 [95% CI, 1.00 to 1.01]), increased symptom bother or worry (IRR, 1.06 [95% CI, 1.03 to 1.08]), a more extroverted personality (IRR, 1.12 [95% CI, 1.03 to 1.08]), greater life satisfaction (IRR, 1.01 [95% CI, 1.00 to 1.02]), and any prior encounter with the visit physician (IRR, 1.17 [95% CI, 1.04 to 1.32]).ConclusionsPrimary care physicians should expect a greater frequency of requests from older patients, patients with greater symptoms bother or worry, more extroverted patients, patients with greater global life satisfaction, and patients with whom they have had prior visits

Dopamine D2 receptor signaling on iMSNs is required for initiation and vigor of learned actions

Striatal dopamine D2 receptors (D2Rs) are important for motor output. Selective deletion of D2Rs from indirect pathway-projecting medium spiny neurons (iMSNs) impairs locomotor activities in a task-specific manner. However, the role of D2Rs in the initiation of motor actions in reward seeking and taking is not fully understood, and there is little information about how receptors contribute under different task demands and with different outcome types. The iMSN-D2Rs modulate neuronal activity and synaptic transmission, exerting control on circuit functions that may play distinct roles in action learning and performance. Selective deletion of D2Rs on iMSNs resulted in slower action initiation and response rate in an instrumental conditioning task, but only when performance demand was increased. The iMSN-Drd2KO mice were also slower to initiate swimming in a T-maze procedural learning task but were unimpaired in cognitive function and behavioral flexibility. In contrast, in a Pavlovian discrimination learning task, iMSN-Drd2KO mice exhibited normal acquisition and extinction of rewarded responding. The iMSN-Drd2KO mice showed performance deficits at all phases of rotarod skill learning. These findings reveal that dopamine modulation through iMSN-D2Rs influences the ability to self-initiate actions, as well as the willingness and/or vigor with which these responses are performed. However, these receptors seem to have little influence on simple associative learning or on stimulus-driven responding. The loss of normal D2R roles may contribute to disorders in which impaired dopamine signaling leads to hypokinesia or impaired initiation of specific voluntary actions

Modified full-face snorkel mask as COVID-19 personal protective equipment: Quantitative results

The COVID-19 crisis has resulted in a shortage of personal protective equipment (PPE). Adapting commercially available full-faced snorkel masks has been proposed as an alternative to narrow the gap in PPE. An advantage of the full-faced snorkel mask design is that it serves two critical purposes: eye and face protection, and high quality air filtration to protect against SARS-CoV-2. We performed quantitative testing on various full-faced snorkel masks with 3D printed adapters that accept commercially available particulate filters, and report on a design that passed Occupational Safety and Health Administration (OSHA) full-facepiece respirator standards