Health-care workforce implications of the Dobbs v Jackson Women's Health Organization decision.

The Dobbs v Jackson Women's Health Organization Supreme Court decision, which revoked the constitutional right to abortion in the USA, has impacted the national medical workforce. Impacts vary across states, but providers in states with restrictive abortion laws now must contend with evolving legal and ethical challenges that have the potential to affect workforce safety, mental health, education, and training opportunities, in addition to having serious impacts on patient health and far-reaching societal consequences. Moreover, Dobbs has consequences on almost every facet of the medical workforce, including on physicians, nurses, pharmacists, and others who work within the health-care system. Comprehensive research is urgently needed to understand the wide-ranging implications of Dobbs on the medical workforce, including legal, ethical, clinical, and psychological dimensions, to inform evidence-based policies and standards of care in abortion-restrictive settings. Lessons from the USA might also have global relevance for countries facing similar restrictions on reproductive care.

Societal implications of the Dobbs v Jackson Women's Health Organization decision.

On June 24, 2022, the US Supreme Court's decision in Dobbs v Jackson Women's Health Organization marked the removal of the constitutional right to abortion in the USA, introducing a complex ethical and legal landscape for patients and providers. This shift has had immediate health and equity repercussions, but it is also crucial to examine the broader impacts on states, health-care systems, and society as a whole. Restrictions on abortion access extend beyond immediate reproductive care concerns, necessitating a comprehensive understanding of the ruling's consequences across micro and macro levels. To mitigate potential harm, it is imperative to establish a research agenda that informs policy making and ensures effective long-term monitoring and reporting, addressing both immediate and future impacts.

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update.

Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A2A- and A2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.

Selective Serotonin Reuptake Inhibitors within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).

Adenosine A2A receptor activation reduces chondrocyte senescence.

Osteoarthritis (OA) pathogenesis is associated with reduced chondrocyte homeostasis and increased levels of cartilage cellular senescence. Chondrosenescence is the development of cartilage senescence that increases with aging joints and disrupts chondrocyte homeostasis and is associated with OA. Adenosine A2A receptor (A2AR) activation in cartilage via intra-articular injection of liposomal A2AR agonist, liposomal-CGS21680, leads to cartilage regeneration in vivo and chondrocyte homeostasis. A2AR knockout mice develop early OA isolated chondrocytes demonstrate upregulated expression of cellular senescence and aging-associated genes. Based on these observations, we hypothesized that A2AR activation would ameliorate cartilage senescence. We found that A2AR stimulation of chondrocytes reduced beta-galactosidase staining and regulated levels and cell localization of common senescence mediators p21 and p16 in vitro in the human TC28a2 chondrocyte cell line. In vivo analysis similarly showed A2AR activation reduced nuclear p21 and p16 in obesity-induced OA mice injected with liposomal-CGS21680 and increased nuclear p21 and p16 in A2AR knockout mouse chondrocytes compared to wild-type mice. A2AR agonism also increased activity of the chondrocyte Sirt1/AMPK energy-sensing pathway by enhancing nuclear Sirt1 localization and upregulating T172-phosphorylated (active) AMPK protein levels. Lastly, A2AR activation in TC28a2 and primary human chondrocytes reduced wild-type p53 and concomitantly increased p53 alternative splicing leading to increase in an anti-senescent p53 variant, Δ133p53α. The results reported here indicate that A2AR signaling promotes chondrocyte homeostasis in vitro and reduces OA cartilage development in vivo by reducing chondrocyte senescence.

Effectiveness of population-based recovery actions for threatened southern mountain caribou.

Habitat loss is affecting many species, including the southern mountain caribou (Rangifer tarandus caribou) population in western North America. Over the last half century, this threatened caribou population's range and abundance have dramatically contracted. An integrated population model was used to analyze 51 years (1973-2023) of demographic data from 40 southern mountain caribou subpopulations to assess the effectiveness of population-based recovery actions at increasing population growth. Reducing potential limiting factors on threatened caribou populations offered a rare opportunity to identify the causes of decline and assess methods of recovery. Southern mountain caribou abundance declined by 51% between 1991 and 2023, and 37% of subpopulations were functionally extirpated. Wolf reduction was the only recovery action that consistently increased population growth when applied in isolation, and combinations of wolf reductions with maternal penning or supplemental feeding provided rapid growth but were applied to only four subpopulations. As of 2023, recovery actions have increased the abundance of southern mountain caribou by 52%, compared to a simulation with no interventions. When predation pressure was reduced, rapid population growth was observed, even under contemporary climate change and high levels of habitat loss. Unless predation is reduced, caribou subpopulations will continue to be extirpated well before habitat conservation and restoration can become effective.

Examining co-occurring social anxiety in cognitive behavioral therapy for eating disorders: Does it change and does it moderate eating disorder outcomes?

OBJECTIVE: Eating disorders (EDs) often co-occur with social anxiety disorder (SAD). However, little research has examined the influence of SAD symptoms on ED treatment outcomes in the context of individual outpatient cognitive-behavior therapy for eating disorders (CBT-ED). It is plausible that SAD symptom severity could improve as a result of ED treatment, given the high overlap between EDs and SAD. We sought to test whether baseline SAD symptoms moderate early response to CBT-ED or post-treatment outcomes in CBT-ED, and the degree to which SAD symptoms improve during therapy despite SAD not being an explicit treatment target. METHOD: ED clients (N = 226) aged ≥16 years were treated with CBT-ED. Outcomes were ED symptoms, clinical impairment, and SAD symptoms measured at baseline, session 5 and post-treatment. RESULTS: Baseline SAD was a weak moderator of early and post-treatment ED symptoms and impairment. SAD symptoms improved moderately over treatment among clients who started with elevated levels of SAD symptomology. DISCUSSION: Clients with EDs can experience good therapeutic outcomes regardless of their social anxiety severity at pre-treatment. SAD symptoms reduced over CBT-ED, but protocol enhancements such as exposure-based strategies that directly target co-occurring social-evaluative concerns may help achieve larger reductions in SAD symptoms. PUBLIC SIGNIFICANCE: Eating disorders often co-occur with anxiety disorders such as social anxiety. We found people who had both social anxiety and an eating disorder benefited as much from eating disorder treatment as people who did not have social anxiety. People who were socially anxious became less anxious as a by-product of receiving eating disorder treatment. It may be possible to reduce social anxiety further by enhancing eating disorder treatment protocols.

The relationships among working alliance, group cohesion and homework engagement in group cognitive behaviour therapy for social anxiety disorder.

OBJECTIVE: Few studies have investigated the role of generic relational factors, such as group cohesion and working alliance, in group cognitive behaviour therapy (CBT) for social anxiety disorder (SAD). The aim of this study was to examine the temporal associations among working alliance, group cohesion, and an index of a CBT-specific factor, homework engagement, as correlates of fear of negative evaluation and symptoms of social anxiety in group CBT for SAD. METHOD: There were 105 participants with a diagnosis of social anxiety disorder who were randomly assigned to 12 sessions of group imagery-enhanced or standard CBT. Participants completed measures at various time points during the 12-session interventions, and the relationship among variables was examined through random-intercept cross-lagged panel models. RESULTS: Group cohesion was significantly associated with social anxiety symptoms at the end of treatment, however there was no significant relationship with working alliance. Greater homework engagement predicted lower social interaction anxiety, but only during mid-treatment. CONCLUSION: The results highlight the importance of supporting group cohesion and maximising homework engagement during core components of social anxiety treatment such as behavioural experiments.

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596.

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor.

Current Smoking and Risk of Coronavirus Infection and Illness in a Highly Controlled Challenge Study: A Re-analysis of the British Cold Study.

INTRODUCTION: Meta-analyses have shown an association between smoking and the risk of Coronavirus Disease 2019 (COVID-19) disease severity, but the risk of smoking and coronavirus infection is less clear. AIMS AND METHODS: We re-analyzed data from the British Cold Study, a 1986-1989 challenge study that exposed 399 healthy adults to 1 of 5 "common cold" viruses (including n = 55 for coronavirus 229E). Participants with cotinine levels below 15 ng/mL (noncurrent smokers) were compared with participants with higher cotinine levels or self-reported smoking (current smokers). We calculated overall and coronavirus-specific unadjusted and adjusted relative risks (RRs) for current smoking and each outcome (infection and illness), and tested whether each association was modified by the type of respiratory virus. RESULTS: Current smokers had a higher adjusted risk than noncurrent smokers for infection (adjusted RR [aRR] = 1.12, 95% CI: 1.01, 1.25) and illness (aRR = 1.48, 95% CI: 1.11, 1.96). Neither association was modified by an interaction term for smoking and type of virus (infection: p = .44, illness: p = .70). The adjusted RR estimates specific to coronavirus 229E for infection (aRR = 1.22, 95% CI: .91, 1.63) and illness (RR = 1.14, 95% CI: .62, 2.08) were not statistically significant. CONCLUSIONS: These RRs provide estimates of the strength of associations between current smoking and infection and illness that can be used to guide tobacco control decisions. IMPLICATIONS: Systematic reviews and meta-analyses have found an association between smoking and COVID-19 disease severity, but fewer studies have examined infection and illness. The British Cold Study, a high-quality challenge study that exposed healthy volunteers to respiratory viruses including a coronavirus, provides an opportunity to estimate the RR for current smoking and infection and illness from coronaviruses and other viruses to guide tobacco control decisions. Compared with noncurrent smokers, current smokers had a 12% increased risk of having a laboratory-confirmed infection and a 48% increased risk of a diagnosed illness, which was not modified by the type of respiratory virus including a coronavirus.

The ecology of human-carnivore coexistence.

With a shrinking supply of wilderness and growing recognition that top predators can have a profound influence on ecosystems, the persistence of large carnivores in human-dominated landscapes has emerged as one of the greatest conservation challenges of our time. Carnivores fascinate society, yet these animals pose threats to people living near them, resulting in high rates of carnivore death near human settlements. We used 41 y of demographic data for more than 2,500 brown bears-one of the world's most widely distributed and conflict-prone carnivores-to understand the behavioral and demographic mechanisms promoting carnivore coexistence in human-dominated landscapes. Bear mortality was high and unsustainable near people, but a human-induced shift to nocturnality facilitated lower risks of bear mortality and rates of conflict with people. Despite these behavioral shifts, projected population growth rates for bears in human-dominated areas revealed a source-sink dynamic. Despite some female bears successfully reproducing in the sink areas, bear persistence was reliant on a supply of immigrants from areas with minimal human influence (i.e., wilderness). Such mechanisms of coexistence reveal a striking paradox: Connectivity to wilderness areas supplies bears that likely will die from people, but these bears are essential to avert local extirpation. These insights suggest carnivores contribute to human-carnivore coexistence through behavioral and demographic mechanisms, and that connected wilderness is critical to sustain coexistence landscapes.

Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-Methadone for Use in Cells, Organelles, and Biofluids.

We report a reagentless, intensity-based S-methadone fluorescent sensor, iS-methadoneSnFR, consisting of a circularly permuted GFP inserted within the sequence of a mutated bacterial periplasmic binding protein (PBP). We evolved a previously reported nicotine-binding PBP to become a selective S-methadone-binding sensor, via three mutations in the PBP's second shell and hinge regions. iS-methadoneSnFR displays the necessary sensitivity, kinetics, and selectivity─notably enantioselectivity against R-methadone─for biological applications. Robust iS-methadoneSnFR responses in human sweat and saliva and mouse serum enable diagnostic uses. Expression and imaging in mammalian cells demonstrate that S-methadone enters at least two organelles and undergoes acid trapping in the Golgi apparatus, where opioid receptors can signal. This work shows a straightforward strategy in adapting existing PBPs to serve real-time applications ranging from subcellular to personal pharmacokinetics.

Coordination of pancreatic islet rhythmic activity by delayed negative feedback.

Secretion of insulin from the pancreas is pulsatile, driven by intrinsic oscillations within individual islets of Langerhans. The secretions are coordinated among the many islets distributed throughout the pancreas producing a synchronized rhythm in vivo that is essential for maintaining normal glucose levels. One hypothesized mechanism for the coordination of islet activity is negative feedback, whereby sequestration of glucose in response to elevated insulin leads to a reduction in the blood glucose level that is sensed by the islet population. This global signal of glucose then coordinates the individual islets. In this study, we tested how this coordination mechanism is affected by time delays in the negative feedback, using a microfluidic system to monitor Ca2+ levels in a small population of islets and implementing glucose control through a negative feedback system. We found that islet synchronization occurs even with time delays in the feedback of up to 7 min. We also found that a second, slower closed-loop oscillation period is produced during delayed feedback in which islet oscillations are clustered into episodes. The period of this second oscillatory mode increases with the time delay and appears to be a second stable behavior that coexists with the faster synchronized oscillation. The general conclusion is that islet coordination through negative feedback is a viable means of islet coordination that is robust to delays in the timing of the feedback, and could complement other potential coordination mechanisms such as entrainment by pancreatic ganglia.NEW & NOTEWORTHY Insulin secretion from islets of Langerhans is rhythmic, and these rhythms are coordinated to produce oscillatory plasma insulin levels. Using a combination of microfluidics and computational modeling, we demonstrate that coordination can occur through negative feedback of the type provided by the liver, even if that feedback is delayed by several minutes. We also demonstrate that a second, slower, mode of oscillations can occur when feedback is delayed where faster oscillations are grouped into episodes.

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

Imagery-enhanced v. verbally-based group cognitive behavior therapy for social anxiety disorder: a randomized clinical trial.

BACKGROUND: Cognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes. METHODS: A randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up. RESULTS: Intention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09-2.62), with no between-treatment differences on this outcome or clinician-rated severity [1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65], SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up). CONCLUSIONS: Group IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.

Saving endangered species using adaptive management.

Adaptive management is a powerful means of learning about complex ecosystems, but is rarely used for recovering endangered species. Here, we demonstrate how it can benefit woodland caribou, which became the first large mammal extirpated from the contiguous United States in recent history. The continental scale of forest alteration and extended time needed for forest recovery means that relying only on habitat protection and restoration will likely fail. Therefore, population management is also needed as an emergency measure to avoid further extirpation. Reductions of predators and overabundant prey, translocations, and creating safe havens have been applied in a design covering >90,000 km2 Combinations of treatments that increased multiple vital rates produced the highest population growth. Moreover, the degree of ecosystem alteration did not influence this pattern. By coordinating recovery involving scientists, governments, and First Nations, treatments were applied across vast scales to benefit this iconic species.

Eprinomectin 5% w/v extended-release injection for the treatment of larval and/or adult Bunostomum phlebotomum, Haemonchus contortus, H. placei, Nematodirus helvetianus, Oesophagostomum radiatum, and Trichostrongylus colubriformis infections in cattle.

In an effort to generate data for regulatory purposes on the therapeutic efficacy of eprinomectin 5% w/v extended-release injection (Eprinomectin ERI) (LongRange®, Boehringer Ingelheim) against infections of immature and adult stages of some nematode species (or stages) which are generally less common or predominantly seen in younger cattle, nine studies (minimum two per parasite and stage) were conducted in the USA and Germany. A total of 218 young cattle were included in seven experimentally induced infection studies (180 animals) and two studies with naturally acquired nematode infections (38 animals), which were compliant with WAAVP and VICH guidelines. In each study, cattle were randomly assigned into groups which received 1 mL per 50 kg body weight of either saline (controls) or Eprinomectin ERI (equivalent to 1 mg eprinomectin per kg body weight) via subcutaneous injection when the parasites were developing fourth-stage larval (L4) or adult nematodes. Following necropsy and parasite recovery, percentage efficacy was calculated based on the comparison of geometric mean nematode counts of the Eprinomectin ERI- vs. the saline-treated animals. Eprinomectin ERI-treated cattle had significantly (p < 0.05) lower counts of each species and stage of nematodes than the controls. Eprinomectin ERI treatment was demonstrated to be efficacious (> 90%) against L4 and adult Bunostomum phlebotomum and Nematodirus helvetianus; against L4 Haemonchus placei, Oesophagostomum radiatum, and Trichostrongylus colubriformis; and against adult H. contortus. Percentage efficacy against L4 H. contortus was variable (69.6 to 100%). All treatments were well accepted, and no treatment-related health problems were observed in any study.

Do composite resin polishing systems damage enamel?

Finishing and polishing of composite resin restorations may cause damage to the bordering enamel. Although many studies have investigated the effect of polish on restorative materials, few have quantified the effect on bordering enamel. The objective of this study was to compare enamel loss surrounding composite restorations after finishing and polishing sequences. The null hypothesis was that there would be no difference in enamel loss between different finishing and polishing sequences. Class V preparations on the buccal and lingual surfaces of 15 extracted human molars were restored with a composite resin and assigned to 1 of 2 finishing and polishing sequences, so that each tooth underwent both sequences (n = 15 per sequence). In sequence 1, a tungsten carbide finishing bur and aluminum oxide polishing discs were used; in sequence 2, a diamond finishing bur, aluminum oxide-impregnated finishing cup, and diamond-impregnated polishing cup were used. Tooth surfaces were scanned with an optical scanner after preparation, finishing, initial polishing, and final polishing. The finishing and polishing scans were aligned to the preparation scan using Cumulus software. The depth of enamel surface loss was calculated and statistically analyzed (α = 0.05; paired t test). Most enamel loss (mean [SD]) resulted from the finishing step with the tungsten carbide bur (51.8 [21.3] µm) or diamond bur (43.3 [12.6] µm). Each polishing step increased mean enamel loss by only a few microns. There was no statistically significant difference between the 2 finishing and polishing sequences. The majority of enamel damage during finishing and polishing of composite resin restorations resulted from the finishing burs. Little enamel was removed by either of the tested composite resin polishing systems.

Deep photothermal effect induced by stereotactic laser beams in highly scattering media.

Plasmonic photothermal therapy (PPTT), as an increasingly studied treatment alternative, has been widely regarded mostly as a surface tissue treatment choice. Although some techniques have been implemented for interstitial tumors, these involve some grade of invasiveness, as the outer skin is usually broken to introduce light-delivering optical fibers or even catheters. In this work, we present a potential non-invasive strategy using the stereotactic approach, long employed in radiosurgery, by converging multiple near infrared laser beams for PPTT in tissue-equivalent optical phantoms that enclose small gel spheres and simulate interstitial tissue impregnated with plasmonic nanoparticles. The real-time in-depth monitoring of temperature increase is realized by an infrared camera face-on mounted over the phantom. Our results show that a significant reduction in the surface heating can be achieved with this configuration while remarkably increasing the interstitial reach of PPTT, assuring a ∼6∘C temperature increase for the simulated tumors at 10 mm depth and ∼4∘C at 15 mm depth and opening up new possibilities for future clinical applications.

Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury.

In OA chondrocytes, there is diminished mitochondrial production of ATP and diminished extracellular adenosine resulting in diminished adenosine A2A receptor (A2AR) stimulation and altered chondrocyte homeostasis which contributes to the pathogenesis of OA. We tested the hypothesis that A2AR stimulation maintains or enhances mitochondrial function in chondrocytes. The effect of A2AR signaling on mitochondrial health and function was determined in primary murine chondrocytes, a human chondrocytic cell line (T/C-28a2), primary human chondrocytes, and a murine model of OA by transmission electron microscopy analysis, mitochondrial stress testing, confocal live imaging for mitochondrial inner membrane polarity, and immunohistochemistry. In primary murine chondrocytes from A2AR-/- null mice, which develop spontaneous OA by 16 weeks, there is mitochondrial swelling, dysfunction, and reduced mitochondrial content with increased reactive oxygen species (ROS) burden and diminished mitophagy, as compared to chondrocytes from WT animals. IL-1-stimulated T/C-28a2 cells treated with an A2AR agonist had reduced ROS burden with increased mitochondrial dynamic stability and function, findings which were recapitulated in primary human chondrocytes. In an obesity-induced OA mouse model, there was a marked increase in mitochondrial oxidized material which was markedly improved after intraarticular injections of liposomal A2AR agonist. These results are consistent with the hypothesis that A2AR ligation is mitoprotective in OA.