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Neural signatures of model-based and model-free reinforcement learning across prefrontal cortex and striatum

Elife. 2026 Jun 22;14:RP106032. doi: 10.7554/eLife.106032.

ABSTRACT

Animals integrate knowledge about how the state of the environment evolves to choose actions that maximise reward. Such goal-directed behaviour – or model-based (MB) reinforcement learning (RL) – can flexibly adapt choice to changes, being thus distinct from simpler habitual – or model-free (MF) RL – strategies. Previous inactivation and neuroimaging work implicates prefrontal cortex (PFC) and the caudate striatal region in MB-RL; however, details are scarce about its implementation at the single-neuron level. Here, we recorded from two PFC regions – the dorsal anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC), and two striatal regions, caudate and putamen – while two rhesus macaques performed a sequential decision-making (two-step) task in which MB-RL involves knowledge about the statistics of reward and state transitions. All four regions, but particularly the ACC, encoded the rewards received and tracked the probabilistic state transitions that occurred. However, ACC (and to a lesser extent caudate) encoded the key variables of the task – namely the interaction between reward, transition, and choice – which underlies MB decision-making. ACC and caudate neurons also encoded MB-derived estimates of choice values. Moreover, caudate value estimates of the choice options flipped when a rare transition occurred, demonstrating value update based on structural knowledge of the task. The striatal regions were unique (relative to PFC) in encoding the current and previous rewards with opposing polarities, reminiscent of dopaminergic neurons, and indicative of an MF prediction error. Our findings provide a deeper understanding of selective and temporally dissociable neural mechanisms underlying goal-directed behaviour.

PMID:42329682 | DOI:10.7554/eLife.106032

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Prevalence and Associations of Medical Expenditure Panel Survey-Defined Long COVID Among Adults: Cross-Sectional Study

JMIR Form Res. 2026 Jun 22;10:e92323. doi: 10.2196/92323.

ABSTRACT

BACKGROUND: Long COVID is a clinical condition that significantly influences quality of life, productivity, and morbidity in the individuals affected. Much of the research to date has examined medical comorbidities and their associations with long COVID, but there remains a substantial need to understand the social and behavioral factors associated with long COVID.

OBJECTIVE: The objective of this study was to investigate the prevalence and associations of Medical Expenditure Panel Survey (MEPS)-defined long COVID among adults in the United States through the application of the Andersen behavioral model.

METHODS: This cross-sectional database study used the 2022 MEPS dataset. Variables in this analysis were organized according to the Andersen behavioral model. The appropriate weighting variable was used to obtain weighted population-based estimates. Between-group differences (ie, those with MEPS-defined long COVID vs those without) were assessed using chi-square tests, and a multivariable binomial logistic regression model was developed to assess the association between each variable and having MEPS-defined long COVID.

RESULTS: A total of 11,266 individuals were eligible for inclusion in this study. This represented a weighted population of 256,500,584 American adults. Of these 11,266 individuals, 790 (7%; weighted population=18,397,214) had MEPS-defined long COVID, whereas 10,476 (93%; weighted population=238,103,371) did not. Variables identified that were statistically associated with having MEPS-defined long COVID among American adults included 3 predisposing variables (age, sex, and Asian race), 2 enabling variables (marital status and employment status), 3 need variables (number of chronic conditions, health status, and instrumental activity of daily living limitations), 1 personal health practices variable (ever receiving the COVID-19 vaccine), and 1 external environmental variable (south region).

CONCLUSIONS: The prevalence and factors associated with having MEPS-defined long COVID among American adults in this study offer insights to expand our limited understanding of the complex environmental and social factors associated with MEPS-defined long COVID. Further research is required among the long COVID population to better understand and differentiate the causes and consequences of this condition.

PMID:42329675 | DOI:10.2196/92323

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Macro Monte Carlo dose calculation for very high energy electron (VHEE) radiotherapy

Med Phys. 2026 Jul;53(7):e70539. doi: 10.1002/mp.70539.

ABSTRACT

BACKGROUND: Very high energy electron (VHEE) radiotherapy has gained growing interest owing to its potential to reach deep-seated targets and induce FLASH effect. Dose calculations can be performed using analytical or Monte Carlo (MC) methods. Analytical approaches enable rapid dose computation but suffer from limited accuracy in heterogeneous media, whereas MC methods provide high accuracy at the expense of substantial computational cost. Macro Monte Carlo (MMC) is a local-to-global method designed to improve dose calculation efficiency compared to general-purpose MC methods. In MMC, particle transport is based on precalculated transport data generated with general-purpose MC simulations on specific geometries, which is subsequently used to model particle transport over macroscopic steps within the absorber, avoiding computationally expensive microscopic tracking. MMC made it to a standard electron dose calculation engine in a commercial treatment planning system. However, to date, MMC has not been investigated for electron energies above 25 MeV.

PURPOSE: To develop and validate an MMC framework for VHEE radiotherapy that improves dose calculation efficiency while preserving accuracy compared to general-purpose MC methods for electron energies up to 250 MeV.

METHODS: Local simulations were performed using EGSnrc with monoenergetic electron pencil beams incident perpendicularly on spherical geometries (0.2-25 MeV) with radii of 0.5-3 mm, and slab geometries (25-250 MeV) of 2 mm thickness, composed of various materials. Physical quantities including energy loss, lateral displacement, and angular distributions of primary and secondary particles were scored and stored in a database. This database was subsequently used to transport electrons step-by-step in the global simulations, employing slab-based transport at energies ≥25 MeV and switching to spherical geometries for electron energies <25 MeV to account for increased scattering. Energy deposition was scored in a 3D dose grid. MMC dose calculations were validated against EGSnrc for monoenergetic VHEE beams (50-250 MeV) incident on homogeneous and heterogeneous slab phantoms, using pencil beams, parallel spot beams with 1 mm radius, and parallel beams with a field size of 5 × 5 cm2. MMC and EGSnrc dose calculations were also performed for two patient CT datasets. Comparisons between MMC and EGSnrc were conducted using integrated depth dose curves, lateral dose profiles, and 3D gamma analysis with 2%/1 mm and 2%/2 mm (global) criteria and a 10% dose threshold. All simulations were performed with statistical uncertainties below 1%, and computation times were recorded.

RESULTS: Integrated depth dose curves and lateral dose profiles agreed within 2% of the maximum dose for all cases considered. For homogeneous and heterogeneous phantoms, MMC dose distributions yielded gamma passing rates above 97% (2%/1 mm) and 99% (2%/2 mm), respectively, compared to EGSnrc. For patient CT datasets, gamma passing rates exceeded 94% (2%/1 mm) and 97% (2%/2 mm). Overall, MMC achieved up to a 27-fold improvement in dose calculation efficiency compared to EGSnrc.

CONCLUSIONS: An MMC framework for VHEE dose calculation was successfully developed and validated for electron energies up to 250 MeV. The method demonstrated good agreement with EGSnrc while providing up to an order-of-magnitude improvement in dose calculation efficiency for the studied cases.

PMID:42329660 | DOI:10.1002/mp.70539

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Timing of Antidiabetic Medication Initiation and Risk of Cardiovascular Events and Mortality

JAMA Netw Open. 2026 Jun 1;9(6):e2619362. doi: 10.1001/jamanetworkopen.2026.19362.

ABSTRACT

IMPORTANCE: Among individuals who meet the diagnostic threshold for type 2 diabetes (T2D), timely initiation of antidiabetic medication (ADM) is essential for lowering long-term cardiovascular risk.

OBJECTIVE: To estimate the association between ADM initiation timing-specifically within 3, 6, or 12 months-and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among individuals newly meeting diagnostic criteria for T2D.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used target trial emulation to analyze health screening data linked to health insurance claims in Korea (2013-2022) using a clone-censor-weight approach. Participants were adults with newly detected glycated hemoglobin (HbA1c) of 6.5% or greater or fasting plasma glucose of 126 mg/dL or greater. Data analysis was conducted from January to August 2025.

EXPOSURES: Eligible participants were cloned into 4 treatment strategies: ADM initiation within 3, 6, or 12 months or no initiation within 12 months (strategy 1, 2, 3, and control, respectively).

MAIN OUTCOMES AND MEASURES: Five-year absolute risk difference (RD) and risk ratio (RR) of 3-point MACE (stroke, myocardial infarction, and all-cause mortality) and all-cause mortality were estimated using Kaplan-Meier survival probabilities along with 95% CIs from 1000-sample nonparametric bootstrapping.

RESULTS: A total of 23 452 eligible participants (mean [SD] age, 48.2 [11.1] years; 5790 [24.7%] female; mean [SD] HbA1c, 6.9% [1.1%]) were cloned into 4 treatment strategies. Earlier ADM initiation compared with the control showed progressively lower point estimates for 3-point MACE (RR, 0.32; 95% CI, 0.15 to 1.11 for strategy 1; RR, 0.65; 95% CI, 0.41 to 1.29 for strategy 2; RR, 0.93; 95% CI, 0.70 to 1.41 for strategy 3), though it did not achieve statistical significance. Corresponding RDs were -0.97% (95% CI, -1.26% to 0.14%), -0.49% (-0.84% to 0.40%), and -0.10% (-0.44% to 0.57%), respectively. ADM initiation within 3 months yielded significant risk reduction for all-cause mortality compared with the control in both relative (RR, 0.31; 95% CI, 0.10-0.98) and absolute (RD, -0.40%; 95% CI, -0.57% to -0.01%) scales.

CONCLUSIONS AND RELEVANCE: In this cohort study, earlier ADM initiation following the diagnostic threshold for T2D showed a lower risk of mortality, suggesting a potential cardiovascular benefit of early glycemic control; however, given the low event counts and the observational nature of the study, further evaluation in larger studies is warranted before definitive conclusions can be drawn.

PMID:42329653 | DOI:10.1001/jamanetworkopen.2026.19362

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International Stakeholder Guidance for Improving Informativeness of Randomized Clinical Trials

JAMA Netw Open. 2026 Jun 1;9(6):e2619487. doi: 10.1001/jamanetworkopen.2026.19487.

ABSTRACT

IMPORTANCE: Many randomized clinical trials are poorly designed, address unimportant questions, or are conducted and reported in ways that limit their usefulness and contribute to research waste. Gaining insight into the perspectives of stakeholders is essential for understanding why issues affecting trial informativeness persist.

OBJECTIVE: To explore global perspectives on enhancing trial informativeness using a 5-point framework including trial importance, design, feasibility, integrity, and reporting.

DESIGN, SETTING, AND PARTICIPANTS: This qualitative study used semistructured, one-on-one interviews conducted via an online video conferencing platform between October 2024 and March 2025. Participants included professionals involved in the funding, design, sponsorship, and regulatory and ethical overview of randomized clinical trials. Demographic characteristics of the 55 participants were analyzed using descriptive statistics.

MAIN OUTCOMES AND MEASURES: The primary outcome was participants’ views on how the informativeness of randomized clinical trials is assessed, why uninformative trials persist, and potential approaches to reduce design and conduct flaws. Data were analyzed thematically, beginning with a deductive coding framework informed by insight from an earlier global rapid review and further refined through inductive coding to capture new themes.

RESULTS: This qualitative study included 55 individuals from 16 countries across 5 continents, primarily from the US (12 [21.8%]) and the United Kingdom (11 [20.0%]), and included investigators (21 [38.2%]), funders (12 [21.8%]), and a range of other stakeholders in randomized clinical trials. Design yielded the greatest number of insights, including further scientific design review after peer review but prior to funding commitment and the need for qualified trial statisticians. Other key insights included building trust through early and meaningful patient partnership (importance) and the need for additional skills-based training beyond good clinical practice to ensure the quality conduct of trials (integrity). Feasibility, often overlooked, was deemed an important factor, with participants stressing the need for compelling, evidence-based plans for recruitment and retention to ensure that research questions are answered reliably.

CONCLUSIONS AND RELEVANCE: In this qualitative study of 55 international stakeholders in randomized clinical trials, interviews offered context and evidence to guide potential improvements in prefunding and peer review processes, as well as in trial design and best practices. Further action is needed to ensure that randomized clinical trials will consistently produce reliable evidence that improves health and strengthens public trust in science.

PMID:42329651 | DOI:10.1001/jamanetworkopen.2026.19487

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Youth Soccer Participation and Brain Health Outcomes in Adolescent Athletes

JAMA Netw Open. 2026 Jun 1;9(6):e2619569. doi: 10.1001/jamanetworkopen.2026.19569.

ABSTRACT

IMPORTANCE: Repetitive head impacts (RHIs) are associated with later-life neurodegeneration. Because soccer is the most widely played sport among youth worldwide, identifying early changes associated with RHI is important.

OBJECTIVE: To determine whether participation in 1 season of youth soccer is associated with changes in cognition, behavior, balance, brain structure or function, or blood biomarkers compared with noncontact sports.

DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study at European centers (Munich, Germany; Leuven, Belgium; and Oslo, Norway). Male adolescent soccer players and noncontact athletes were each studied across a single competitive season with assessments at preseason, postseason, and 2 months later. Data were analyzed from January 2023 to March 2025.

EXPOSURES: Soccer players were compared with noncontact athletes. In addition, self-reported heading of a soccer ball was assessed among soccer players as a measure of RHI.

MAIN OUTCOMES AND MEASURES: Cognition, behavior, balance, magnetic resonance imaging (brain structure, function, and biochemistry), and plasma biomarkers.

RESULTS: Male adolescent soccer players (n = 82; mean [SD] age, 14.8 [0.6] years) did not differ from noncontact sport athletes (n = 47; mean [SD] age, 14.7 [0.7] years) in cognition, behavior, balance, cortical thickness, brain volumes, white-matter microstructure, or functional connectivity. At preseason, soccer players had higher total N-acetylaspartate (tNAA; β, -0.379 [95% CI, -0.627 to -0.131]; P = .003), glial fibrillary acidic protein (GFAP; β, -0.055 [95% CI, -0.103 to -0.006]; P = .03), and neurofilament light chain (NfL; β, -0.071 [95% CI, -0.122 to -0.020]; P = .01) than noncontact sport controls. Across the season, tNAA (β, 0.047 [95% CI, 0.020-0.074]; P = .001) declined in soccer players and increased in controls, converging by postseason. Group trajectories of GFAP and NfL did not differ between groups. Within soccer players, heading exposure was not significantly associated with changes in any outcome.

CONCLUSIONS AND RELEVANCE: In this cohort study of adolescent males, no statistically significant differences were detected over 1 season between soccer players and noncontact sport athletes in cognition, behavior, or brain structure and function. Group differences in GFAP and NfL may represent early signs of exposure, but lack of association with heading exposure warrants further investigation. These results highlight the need for large, multiyear studies to inform health policy.

PMID:42329650 | DOI:10.1001/jamanetworkopen.2026.19569

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Abortion Bans and Pregnancy-Related Care Across Physician Specialties: A Qualitative Study

JAMA Netw Open. 2026 Jun 1;9(6):e2619644. doi: 10.1001/jamanetworkopen.2026.19644.

ABSTRACT

IMPORTANCE: Following the Dobbs v Jackson Women’s Health Organization decision, states with abortion bans have experienced increased maternal morbidity and mortality. However, the associations of these restrictions with abortion-adjacent care-medical care directly affected by or overlapping with abortion, such as management of early pregnancy loss (EPL), ectopic pregnancy, and other pregnancy complications-are not well described.

OBJECTIVE: To examine how state-level abortion bans are associated with abortion-adjacent clinical care among physicians from different medical specialties.

DESIGN, SETTING, AND PARTICIPANTS: This qualitative study was conducted between May 13, 2024, and May 23, 2025, using purposive and snowball sampling. Participants included physicians from emergency medicine, family medicine, and obstetrics and gynecology specialties practicing in 9 states with total abortion bans. Semistructured interviews were conducted via videoconference and analyzed using an inductive thematic approach with dual independent coding.

EXPOSURE: Medical practice in a state with an abortion ban.

MAIN OUTCOMES AND MEASURES: Participant-reported experiences with clinical decision-making, care delivery, counseling practices, and professional responsibilities in the context of abortion bans.

RESULTS: A total of 40 physicians (18 in obstetrics and gynecology, 8 in family medicine, and 14 in emergency medicine) across 9 states participated, 30 (75.0%) of whom were female. Mean (SD) length of time in practice was 7.9 (6.1) years. Six major themes emerged: (1) delays in care and deviations from standard practice for EPL, ectopic pregnancy, molar pregnancy, preterm prelabor rupture of membranes, and maternal comorbidities; (2) ambiguity and fear among physicians; (3) loss of patient autonomy and shared decision-making; (4) erosion of trust in the patient-physician relationship; (5) placement of physicians into new gatekeeping roles; and (6) increased health care system burdens. Physicians described requiring additional confirmatory testing, seeking institutional approval even for emergent life-saving interventions, and being forced to determine which patients were sick enough to receive medically indicated care.

CONCLUSIONS AND RELEVANCE: In this qualitative study of the consequences of abortion bans across multiple medical specialties, abortion bans were associated with disrupted clinical care far beyond what is traditionally categorized as abortion, with treatment delays that endanger patients, undermined patient autonomy and physician-patient trust, and with new gatekeeping roles for physicians. These restrictions shifted medical decision-making from clinical judgment and patient values toward legal risk mitigation, with potential long-term consequences including exacerbation of health care inequities and compromised ability to provide safe and effective care for pregnant patients.

PMID:42329649 | DOI:10.1001/jamanetworkopen.2026.19644

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Multilevel Stewardship Intervention for Use of Anticoagulation-Antiplatelet Therapy

JAMA Intern Med. 2026 Jun 22. doi: 10.1001/jamainternmed.2026.2036. Online ahead of print.

ABSTRACT

IMPORTANCE: Antiplatelet medications are overprescribed in patients taking direct oral anticoagulants (DOACs), increasing their risk of major bleeding. The utility of potentially scalable antithrombotic stewardship approaches remains unknown.

OBJECTIVE: To evaluate a multicomponent antithrombotic stewardship initiative to reduce unnecessary antiplatelet use in patients prescribed DOACs.

DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study used retrospective multiperiod comparative interrupted-time-series analysis from July 2020 to July 2023 to compare intervention and control sites. Participants were adults prescribed DOACs in the ambulatory setting. The interventions occurred in 7 Veterans Health Administration (VHA) health systems, while 128 other VHA health systems served as controls. Data were analyzed from July 2023 to March 2026.

INTERVENTION: In stage 1, lasting 9 months, intervention sites implemented educational outreach to clinicians and patients and changes to the electronic health record system. In stage 2, lasting 16 months, a clinical pharmacist-facing electronic flag identifying patients receiving antiplatelet therapy was added to a widely used electronic dashboard.

MAIN OUTCOMES AND MEASURES: Monthly site-level percentage of patients prescribed antiplatelet medications. The summary measure was the difference in the semiannual change in the outcome for intervention compared with control sites, controlling for preintervention trends. Subgroup analyses were performed based on antiplatelet indication.

RESULTS: This study found that preintervention antiplatelet use in patients prescribed DOACs was 26.1% (95% CI, 26.0%-26.1%) in the 7 intervention sites (27 588 patients; 704 females [2.6%]) and 30.1% (95% CI, 30.0%-30.2%) in 128 control sites (253 085 patients; 6481 females [2.6%]). Antiplatelet use decreased faster by an absolute -0.58 (95% CI, -0.95 to -0.22) percentage points (pp) per 6 months for intervention compared with control sites after the 2 interventions had been implemented. The initial set of interventions was associated with an absolute -0.29 (95% CI, -0.61 to 0.04) pp change per 6 months and later augmentation with the electronic flag was associated with an absolute -0.29 (95% CI, -0.61 to 0.03) pp change per 6 months. The combined interventions were associated with the greatest reduction in the subgroup of patients with stable coronary artery disease (absolute -2.1 [95% CI, -3.0 to -1.2] pp per 6 months, equivalent to a -5.5% additional change compared with the baseline prevalence in this group), for whom antiplatelet deimplementation is likely appropriate.

CONCLUSIONS AND RELEVANCE: This study found that the combined interventions were associated with a clinically meaningful reduction in potentially harmful combination antithrombotic therapy. The initial educational outreach and changes to the electronic health record and later augmentation with the electronic flag had additive effects, highlighting the importance of multilevel interventions to speed adoption of evidence-based antithrombotic prescribing.

PMID:42329643 | DOI:10.1001/jamainternmed.2026.2036

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Influence of the thickness of high-translucency ceramics on the bond strength of a universal resin cement following different storage times

Gen Dent. 2026 Jul-Aug;74(4):70-76.

ABSTRACT

Light transmission during photopolymerization is reduced by the intrinsic optical properties of ceramics, which vary with material and thickness. The higher translucency of lithium disilicate contrasts with the chemical inertness and opacity of third-generation zirconia materials, which often require dual-cure resin cements to ensure adequate polymerization. This study evaluated the influence of the thickness of lithium disilicate and monolithic zirconia ceramics on the bond strength of a universal resin cement following 24 hours and 6 months of water storage. High-translucency lithium disilicate and zirconia discs were milled in 2 thicknesses: 0.5 mm and 1.5 mm (n = 10). Cylinders of light-curing resin cement, 0.7 mm in diameter, were bonded following application of a universal adhesive system. Microshear bond strength testing and failure mode analysis were performed after 24 hours and 6 months of water storage in a temperature-controlled, light-protected environment. Mixed generalized linear models showed that the 1.5-mm zirconia group presented a higher mean bond strength (P < 0.05). The 1.5-mm zirconia group showed significantly higher mean bond strengths than the 1.5-mm lithium disilicate group at both evaluation times (P < 0.05). Both 0.5- and 1.5-mm-thick zirconia discs exhibited a statistically significant reduction in bond strength after 6 months of storage (P < 0.05), whereas lithium disilicate discs in both thicknesses maintained stable bond strengths over time (P > 0.05). The chi-square test revealed a significant association between premature failure and the material group, with no premature failures occurring in the 0.5-mm lithium disilicate group after either storage time. Although the bond strength of zirconia decreased over time, 1.5-mm-thick zirconia still attained a higher value than 1.5-mm-thick lithium disilicate at the 6-month timepoint. Lithium disilicate showed stable values at both thicknesses.

PMID:42329617

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Effect of immediate vs delayed polishing on the surface roughness of microhybrid and nanohybrid composite resins

Gen Dent. 2026 Jul-Aug;74(4):65-68.

ABSTRACT

The aim of this in vitro study was to evaluate the surface roughness of microhybrid and nanohybrid composite resins subjected to polishing procedures immediately after curing or after 24 hours of immersion in distilled water. Two groups, comprising a total of 60 disc-shaped (10 × 2-mm) specimens, were prepared using microhybrid and nanohybrid composite resins (n = 30 per material) and further categorized into subgroups based on the polishing protocol. Specimens were fabricated by packing the appropriate composite resin into a cylindrical mold, compressing the material between transparent polyester film strips at both ends, and curing each side of the specimen with an LED light for 40 seconds. All specimens were finished immediately after polymerization using a 12-fluted tungsten carbide bur in a high-speed handpiece for 15 seconds under water cooling. The specimens in each material group were then divided into 2 subgroups (n = 15 each). One subgroup was polished immediately after finishing; the other was stored in distilled water at 37°C in a dark environment for 24 hours prior to polishing. Polishing was performed using a planar motion with 10 strokes at a low speed of 12,000 rpm, applying light pressure for 30 seconds. Surface roughness (Ra) was analyzed with a profilometer. Independent t tests were performed to compare the Ra data of the groups, and values of P < 0.05 were considered statistically significant. The Ra values of nanohybrid specimens were significantly lower than those of microhybrid specimens, regardless of whether polishing was performed immediately or delayed. Delayed polishing significantly reduced the Ra values of both materials. Nanohybrid composite resins demonstrated superior polishability and surface smoothness, making them a preferred choice for both immediate and delayed polishing.

PMID:42329616