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Introduction: Deprescribing ( medication dose reduction or cessation ) is an integral component of appropriate prescribing. The extent to which deprescribing recommendations are included in clinical practice guidelines is unclear. This scoping review aimed to identify guidelines that contain deprescribing recommendations, qualitatively explore the content and format of deprescribing recommendations and estimate the proportion of guidelines that contain deprescribing recommendations., Methods: Bibliographic databases and Google were searched for guidelines published in English from January 2012 to November 2022. Guideline registries were searched from January 2017 to February 2023. Two reviewers independently screened records from databases and Google for guidelines containing one or more deprescribing recommendations. A 10% sample of the guideline registries was screened to identify eligible guidelines and estimate the proportion of guidelines containing a deprescribing recommendation. Guideline and recommendation characteristics were extracted and language features of deprescribing recommendations including content, form, complexity and readability were examined using a conventional content analysis and the SHeLL Health Literacy Editor tool., Results: 80 guidelines containing 316 deprescribing recommendations were included. Deprescribing recommendations had substantial variability in their format and terminology. Most guidelines contained recommendations regarding for who (75%, n=60) , what (99%, n=89) and when or why (91%, n=73) to deprescribe, however, fewer guidelines (58%, n=46) contained detailed guidance on how to deprescribe. Approximately 29% of guidelines identified from the registries sample (n=14/49) contained one or more deprescribing recommendations., Conclusions: Deprescribing recommendations are increasingly being incorporated into guidelines, however, many guidelines do not contain clear and actionable recommendations on how to deprescribe which may limit effective implementation in clinical practice. A co-designed template or best practice guide, containing information on aspects of deprescribing recommendations that are essential or preferred by end-users should be developed and employed., Trial Registration Number: osf.io/fbex4., Competing Interests: Competing interests: ER receives royalties from UpToDate (Wolters Kluwer) for writing a chapter on deprescribing. WT has received research grants related to deprescribing from the US Deprescribing Network, Canadian Institutes for Health Research and Health Canada. AVL, ER and JPT are members of the executive committee of the Australian Deprescribing Network (ADeN)., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Competing Interests: All authors state they have no perceived or real conflicts of interest to declare.

Background: Sustainable implementation of new professional services into clinical practice can be difficult. In 2019, a population-wide initiative called SaferMedsNL was implemented across the province of Newfoundland and Labrador (NL), to promote appropriate medication use. Two evidence-based interventions were adapted to the context of NL to promote deprescribing of proton pump inhibitors and sedatives. The objective of this study was to identify and prioritize which actions supported the implementation of deprescribing in community practice for pharmacists, physicians and nurse practitioners across the province., Methods: Community pharmacists, physicians and nurse practitioners were invited to participate in virtual focus groups. Nominal Group Technique was used to elicit responses to the question: "What actions support the implementation of deprescribing into the daily workflow of your practice?" Participants prioritized actions within each group while thematic analysis permitted comparison across groups., Results: Five focus groups were held in fall 2020 involving pharmacists ( n = 11), physicians ( n = 7) and nurse practitioners ( n = 4). Participants worked in rural ( n = 10) and urban ( n = 12) settings. The different groups agreed on what the top 5 actions were, with the top 5 receiving 68% of the scores: (1) providing patient education, (2) allocating time and resources, (3) building interprofessional collaboration and communication, (4) fostering patient relationships and (5) aligning with public awareness strategies., Conclusion: Pharmacists, physicians and nurse practitioners identified similar actions that supported implementing evidence-based deprescribing into routine clinical practice. Sharing these strategies may help others embed deprescribing into daily practice and assist the uptake of medication appropriateness initiatives by front-line providers. Can Pharm J (Ott) 2024;157:xx-xx., Competing Interests: All authors state they have no perceived or real conflicts of interest to declare., (© The Author(s) 2024.)

Background: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis., Purpose: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone., Methods: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors., Results: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years)., Limitations: Lack of an external data set for model validation., Conclusion/relevance: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients., Competing Interests: Conflicts of interest Paul Nghiem reports personal fees from Rain Therapeutics, EMD Serono, Pfizer, and Merck; grants from EMD Serono and Bristol-Myers Squibb to his institution outside the submitted work; and a patent for Merkel cell polyomavirus T antigen–specific T-cell receptors and uses thereof pending (University of Washington), as well as a patent for novel epitopes as T-cell targets in Merkel cell carcinoma pending (University of Denmark and University of Washington). No other disclosures were reported., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G&#95;{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G&#95;{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Background: Given the negative environmental impacts of pharmaceuticals, including their contribution to healthcare's carbon footprint, pharmacists have a role in responding to the climate and biodiversity crises. Knowledge and education are required to support transitions to environmentally sustainable pharmacy practice (ESPP). The aim of this study was to explore Australian undergraduate pharmacy students' knowledge and attitudes towards environmental sustainability and ESPP curriculum content., Methods: Participants were surveyed using an anonymous online questionnaire deployed using Qualtrics. The questionnaire comprised of two main sections: the 15-item New Ecological Paradigm (NEP) scale to determine participants' environmental attitude score, and section on students' perceptions and curricular experience of environmentally sustainable practice which was adapted from previously published surveys. The invitation with survey link was disseminated via social media, Australian pharmacy student organisations, and direct approach. Quantitative data were reported descriptively. Qualitative data from responses to open-ended questions were analysed thematically using a reflexive, recursive approach. Incomplete survey responses were excluded from the analysis., Results: Of the 164 complete responses, 99% had previously received information on environmental sustainability. However, only 10% were knowledgeable about ESPP and only 8.5% were aware of ESPP content in their pharmacy school curriculum. Importantly, 70% of respondents saw ESPP as relevant to their future pharmacy practice, and 94% believed the pharmacy profession has a responsibility to undertake sustainability initiatives in the delivery of pharmaceutical care., Conclusions: Australian pharmacy students lacked knowledge of ESPP and few reported having curricular exposure to ESPP content in their pharmacy degrees. Therefore, ESPP content is an important area for development in pharmacy curricula., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s).)

Competing Interests: None disclosed.

Competing Interests: None disclosed.

Importance: Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance., Objective: To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis., Design, Setting, and Participants: This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021., Main Outcomes and Measures: Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses., Results: Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years)., Conclusions and Relevance: In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Background: Initial biopsies of cutaneous squamous cell carcinomas (cSCCs) may not reveal aggressive histologic features, which would otherwise inform appropriate surgical management and patient education., Objective: To assess the incidence of, and risk factors for, histopathologic upgrading of cSCC during Mohs micrographic surgery (MMS)., Methods: This was a retrospective cohort study of invasive cSCCs treated with MMS between 2017 and 2019 at 1 academic institution. An "upgrade" was defined as a lesser degree of differentiation (poor or moderate) and/or bony or perineural invasion identified during MMS that was not reported in histopathologic evaluation of the initial biopsy., Results: Of the 1558 tumors studied, 115 (7.4%) were upgraded during MMS. In multivariate logistic regression analysis, male sex, prior field treatment, location on the ear/lip, rapid growth of cSCC, and tumor diameter ≥2 cm were significant predictors of tumor upgrading. Upgraded tumors were more likely to require ≥3 MMS stages to clear, complicated closure (flap or graft), or outside (referral) repairs., Limitations: Single-center study, retrospective, and inter-rater variability., Conclusions: A significant proportion of cSCCs is histopathologically upgraded with more aggressive features during MMS. Routinely documented patient and tumor characteristics can predict tumor upgrading and assist clinicians in directing the management of potentially high-risk cSCC patients., Competing Interests: Conflicts of interest Dr Council has done consulting/advisory board work for Sanofi-Genzyme/Regeneron. Drs Chung, McEvoy, Rosman, and Hurst, and Author Hoang have no conflicts of interest to declare., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the cost-effectiveness of axillary observation versus sentinel lymph node biopsy (SLNB) after negative axillary ultrasound (AUS). In patients with clinical T1-T2 N0 breast cancer and negative AUS, SLNB is the current standard of care for axillary staging. However, SLNB is costly, invasive, decreasing in importance for medical decision-making, and is not considered therapeutic. Observation alone is currently being evaluated in randomized clinical trials, and is thought to be non-inferior to SLNB for patients with negative AUS., Methods: We performed cost-effectiveness analyses of observation versus SLNB after negative AUS in postmenopausal women with clinical T1-T2 N0, HR + /HER2 - breast cancer. Costs at the 2016 price level were evaluated from a third-party commercial payer perspective using the MarketScan® Database. We compared cost, quality-adjusted life years (QALYs), and net monetary benefit (NMB). Multiple sensitivity analyses varying baseline probabilities, costs, utilities, and willingness-to-pay thresholds were performed., Results: Observation was superior to SLNB for patients with N0 and N1 disease, and for the entire patient population (NMB in US$: $655,659 for observation versus $641,778 for SLNB for the entire patient population). In the N0 and N1 groups, observation incurred lower cost and was associated with greater QALYs. SLNB was superior for patients with > 3 positive lymph nodes, representing approximately 5% of the population. Sensitivity analyses consistently demonstrated that observation is the optimal strategy for AUS-negative patients., Conclusion: Considering both cost and effectiveness, observation is superior to SLNB in postmenopausal women with cT1-T2 N0, HR + /HER2 - breast cancer and negative AUS.

Measuring the thermonuclear burn history is an important way to diagnose inertial fusion implosions. Using the gas Cherenkov detectors at the OMEGA laser facility, we measure the HT fusion burn in a H 2 +T 2 gas-fueled implosion for the first time. Using multiple detectors with varied Cherenkov thresholds, we demonstrate a technique for simultaneously measuring both the HT and DT burn histories from an implosion where the total reaction yields are comparable. This new technique will be used to study material mixing and kinetic phenomena in implosions.

An aerogel Cherenkov detector is proposed to measure the X-ray energy spectrum from the Cygnus-intense flash X-ray source operated at the Nevada National Security Site. An array of aerogels set at a variety of thresholds between 1 and 3 MeV will be adequate to map out the bremsstrahlung X-ray production of the Cygnus, where the maximum energy of the spectrum is normally around 2.5 MeV. In addition to the Cherenkov radiation from aerogels, one possible competing light-production mechanism is optical transition radiation (OTR), which may be significant in aerogels due to the large number of transitions from SiO 2 clusters to vacuum voids. To examine whether OTR is a problem, four aerogel samples were tested using a mono-energetic electron beam (varied in the range of 1-3 MeV) at NSTec Los Alamos Operations. It was demonstrated that aerogels can be used as a Cherenkov medium, where the rate of the light production is about two orders magnitude higher when the electron beam energy is above threshold.

The newest generation of Gas Cherenkov Detector (GCD-3) employed in Inertial Confinement Fusion experiments at the Omega Laser Facility has provided improved performance over previous generations. Comparison of reaction histories measured using two different deuterium-tritium fusion products, namely gamma rays using GCD and neutrons using Neutron Temporal Diagnostic (NTD), have provided added credibility to both techniques. GCD-3 is now being brought to the National Ignition Facility (NIF) to supplement the existing Gamma Reaction History (GRH-6m) located 6 m from target chamber center (TCC). Initially it will be located in a reentrant well located 3.9 m from TCC. Data from GCD-3 will inform the design of a heavily-shielded "Super" GCD to be located as close as 20 cm from TCC. It will also provide a test-bed for faster optical detectors, potentially lowering the temporal resolution from the current ∼100 ps state-of-the-art photomultiplier tubes (PMT) to ∼10 ps Pulse Dilation PMT technology currently under development.

Absolute bang time measurements with the gas Cherenkov detector (GCD) and gamma reaction history (GRH) diagnostic have been performed to high precision at the OMEGA laser facility at the University of Rochester with bang time values for the two diagnostics agreeing to within 5 ps on average. X-ray timing measurements of laser-target coupling were used to calibrate a facility-generated laser timing fiducial with rms spreads in the measured coupling times of 9 ps for both GCD and GRH. Increased fusion yields at the National Ignition Facility (NIF) will allow for improved measurement precision with the GRH easily exceeding NIF system design requirements.

Herpes simplex virus (HSV) infection of many cultured cells, e.g., Vero cells, can be initiated by receptor binding and pH-neutral fusion with the cell surface. Here we report that a major pathway for HSV entry into the HeLa and CHO-K1 cell lines is dependent on endocytosis and exposure to a low pH. Enveloped virions were readily detected in HeLa or receptor-expressing CHO cell vesicles by electron microscopy at <30 min postinfection. As expected, images of virus fusion with the Vero cell surface were prevalent. Treatment with energy depletion or hypertonic medium, which inhibits endocytosis, prevented uptake of HSV from the HeLa and CHO cell surface relative to uptake from the Vero cell surface. Incubation of HeLa and CHO cells with the weak base ammonium chloride or the ionophore monensin, which elevate the low pH of organelles, blocked HSV entry in a dose-dependent manner. Noncytotoxic concentrations of these agents acted at an early step during infection by HSV type 1 and 2 strains. Entry mediated by the HSV receptor HveA, nectin-1, or nectin-2 was also blocked. As analyzed by fluorescence microscopy, lysosomotropic agents such as the vacuolar H(+)-ATPase inhibitor bafilomycin A1 blocked the delivery of virus capsids to the nuclei of the HeLa and CHO cell lines but had no effect on capsid transport in Vero cells. The results suggest that HSV can utilize two distinct entry pathways, depending on the type of cell encountered.