Applications of artificial intelligence for surgical extraction in stomatology: a systematic review.

OBJECTIVES: Artificial intelligence (AI) has been extensively used in the field of stomatology over the past several years. This study aimed to evaluate the effectiveness of AI-based models in the procedure, assessment, and treatment planning of surgical extraction. STUDY DESIGN: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a comprehensive search was conducted on the Web of Science, PubMed/MEDLINE, Embase, and Scopus databases, covering English publications up to September 2023. Two reviewers performed the study selection and data extraction independently. Only original research studies utilizing AI in surgical extraction of stomatology were included. The Cochrane risk of bias tool for randomized trials (RoB 2) was selected to perform the quality assessment of the selected literature. RESULTS: From 2,336 retrieved references, 35 studies were deemed eligible. Among them, 28 researchers reported the pioneering role of AI in segmentation, classification, and detection, aligning with clinical needs. In addition, another 7 studies suggested promising results in tooth extraction decision-making, but further model refinement and validation were required. CONCLUSIONS: Integration of AI in stomatology surgical extraction has significantly progressed, enhancing decision-making accuracy. Combining and comparing algorithmic outcomes across studies is essential for determining optimal clinical applications in the future.

Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.

Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

LKB1 prevents ILC2 exhaustion to enhance antitumor immunity.

Group 2 innate lymphoid cells (ILC2s) play crucial roles in mediating allergic inflammation. Recent studies also indicate their involvement in regulating tumor immunity. The tumor suppressor liver kinase B1 (LKB1) inactivating mutations are associated with a variety of human cancers; however, the role of LKB1 in ILC2 function and ILC2-mediated tumor immunity remains unknown. Here, we show that ablation of LKB1 in ILC2s results in an exhausted-like phenotype, which promotes the development of lung melanoma metastasis. Mechanistically, LKB1 deficiency leads to a marked increase in the expression of programmed cell death protein-1 (PD-1) in ILC2s through the activation of the nuclear factor of activated T cell pathway. Blockade of PD-1 can restore the effector functions of LKB1-deficient ILC2s, leading to enhanced antitumor immune responses in vivo. Together, our results reveal that LKB1 acts to restrain the exhausted state of ILC2 to maintain immune homeostasis and antitumor immunity.

A novel stability criterion and precise control for linear time delay systems based on regional configuration of the poles.

This paper presents the concept of region stability and provides criteria for region stability of linear time delay systems, which can reveal the dynamic and steady-state performance of the systems more precisely. Corresponding design schemes for stabilization and tracking control that can accurately control various performance of time delay systems have also been explored. First, in the light of the connection between the poles and the dynamic properties of the system, the concept of region stability is given to describe the finer dynamic behavior of time delay systems. The criteria for the region stability are also presented. Second, the region stabilization methods are investigated, which can ensure that the system satisfies a certain dynamic performance by setting the eigenvalues in a certain convex region. Third, a precise tracking control of the linear time delay systems is addressed as an application of region stabilization. It can control the steady state performance and transient response of the tracking signal more precisely. Finally, three instances are provided to display the superiority of the new method for the performance indexes of the linear time delay systems.

Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

Risk factors of postoperative cerebral hyperperfusion syndrome and its relationship with clinical prognosis in adult patients with moyamoya disease.

BACKGROUND: To investigate the incidence, risk factors, and clinical prognosis of cerebral hyperperfusion syndrome (CHS) after superficial temporal artery-middle cerebral artery anastomosis combined with encephalo-duro-arterio-synangiosis (STA-MCA/EDAS) in adult patients with moyamoya disease (MMD). METHODS: The clinical data of 160 adult patients with MMD treated by STA-MCA/EDAS from January 2016 to January 2017 were retrospectively analyzed. According to CHS diagnosis, MMD patients were divided into CHS and non-CHS group. Univariate and multivariate analysis of risk factors and Kaplan-Meier curve of stroke-free survival for CHS were performed. RESULTS: A total of 12 patients (7.5%) developed postoperative CHS, of which 4 patients (2.5%) presented with cerebral hemorrhage. Univariate and multivariate analysis showed moyamoya vessel on the surgical hemisphere (OR = 3.04, 95% CI = 1.02-9.03, P = 0.046) and left operated hemisphere (OR = 5.16, 95% CI = 1.09-21.34, P = 0.041) were independent risk factors for CHS. The other variables, such as age, gender, presentation, hypertension, diabetes, smoking, mean mRS score on admission, modified Suzuki stage and pre-infarction stage on surgical hemisphere, and bypass patency, had no association with postoperative CHS (P > 0.05). At final follow-up with average 38 months, there were 18 out of 133 patients (13.5%, 4.91% per person year) presented with newly developed complications. There was no significant difference between newly developed complications, mean mRS scores, and Kaplan-Meier curve of stroke-free survival in patients with and without CHS (P > 0.05). CONCLUSION: The concentration of moyamoya vessels and left operated hemisphere was independent risk factors for CHS, which could not affect the clinical prognosis if treated timely and properly. The current study offers a new perspective of moyamoya vessels and supporting data for choosing MMD candidates on cerebral revascularization.

Treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies and the effects on hormone levels.

BACKGROUND: We aimed to compare the treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies, as well as the effects on hormone levels and clinical symptoms. METHODS: A total of 82 patients with pituitary adenomas that were surgically resected from June 2018 to March 2021 were selected and divided into a group receiving neuroendoscopic trans-sphenoidal pituitary adenomectomy (group A, N.=40), and the other group receiving microscopic surgery (group B, N.=42). Surgery-related indices, hormone levels before discharge and alleviation of symptoms 24 weeks after surgery were compared. RESULTS: Both groups had significantly different degrees of tumor resection (P<0.05). The proportion of cases receiving total adenomectomy in group A significantly exceeded that of group B (P<0.05). The surgical time of group A was significantly longer than that of group B (P<0.05). Group A had significantly shorter mean hospitalization stay than that of group B (P<0.05). The postoperative hormone levels of both groups decreased significantly differently (P<0.05). Before discharge, the hormone recovery rate of group A significantly surpassed that of group B (P<0.05). The hormone levels of cases with prolactinoma, adrenocorticotropic hormone adenoma and growth hormone adenoma in group A dropped more significantly than those of group B did (P<0.05). CONCLUSIONS: Compared with microscopic surgery, neuroendoscopic trans-sphenoidal pituitary adenomectomy worked more effectively, induced fewer postoperative complications and better promoted the postoperative recovery of hormone levels.

Peroxiredoxin 2 Is a Potential Objective Indicator for Severity and the Clinical Status of Subarachnoid Hemorrhage Patients.

Purpose: We have demonstrated that peroxiredoxin 2 (Prx2) released from lytic erythrocytes and damaged neurons into the subarachnoid space could activate microglia and then result in neuronal apoptosis. In this study, we tested the possibility of using Prx2 as an objective indicator for severity of the subarachnoid hemorrhage (SAH) and the clinical status of the patient. Materials and Methods: SAH patients were prospectively enrolled and followed up for 3 months. Cerebrospinal fluid (CSF) and blood samples were collected 0-3 and 5-7 days after SAH onset. The levels of Prx2 in the CSF and the blood were measured by an enzyme-linked immunosorbent assay (ELISA). We used Spearman's rank coefficient to assess the correlation between Prx2 and the clinical scores. Receiver operating characteristic (ROC) curves were used for Prx2 levels to predict the outcome of SAH by calculating the area under the curve (AUC). Unpaired Student's t-test was used to analyze the differences in continuous variables across cohorts. Results: Prx2 levels in the CSF increased after onset while those in the blood decreased. Existing data showed that Prx2 levels within 3 days in the CSF after SAH were positively correlated with the Hunt-Hess score (R = 0.761, P < 0.001). Patients with CVS had higher levels of Prx2 in their CSF within 5-7 days after onset. Prx2 levels in the CSF within 5-7 days can be used as a predictor of prognosis. The ratio of Prx2 in the CSF and the blood within 3 days of onset was positively correlated with the Hunt-Hess score and negatively correlated with Glasgow Outcome Scale (GOS; R = -0.605, P < 0.05). Conclusion: We found that the levels of Prx2 in the CSF and the ratio of Prx2 in the CSF and the blood within 3 days of onset can be used as a biomarker to detect the severity of the disease and the clinical status of the patient.

PLZF restricts intestinal ILC3 function in gut defense.

Group 3 innate lymphoid cells (ILC3s) play important roles in maintaining intestinal homeostasis by protecting the host from pathogen infections and tissue inflammation. The transcription factor PLZF (promyelocytic leukemia zinc finger), encoded by zinc finger BTB domain containing 16 (Zbtb16), is highly and transiently expressed in ILC precursors (ILCPs). However, the role of PLZF in regulating ILC3 development and function remains unknown. Here, we show that PLZF was specifically expressed in mature intestinal ILC3s compared with other ILC subsets. PLZF was dispensable for ILC3 development. However, PLZF deficiency in ILC3s resulted in increased innate interleukin-22 (IL-22) secretion and protection against gut infection and inflammation. Mechanistically, PLZF negatively regulated IL-22 expression by ILC3s in a cell-intrinsic manner by binding to the IL-22 promoter region for transcriptional repression. Together, our data suggest that PLZF restricts intestinal ILC3 function to regulate gut immune homeostasis.

Influential factors and transcriptome analyses of immature diploid embryo anthocyanin accumulation in maize.

BACKGROUND: Anthocyanins are widely applied as a marker for haploid identification after haploid induction in maize. However, the factors affecting anthocyanin biosynthesis in immature embryos and the genes regulating this process remain unclear. RESULTS: In this study, we analyzed the influence of genetic background of the male and female parents, embryo age and light exposure on anthocyanin accumulation in embryos. The results showed that light exposure was the most crucial factor enhancing the pigmentation of immature embryos. The identification accuracy of haploid embryos reached 96.4% after light exposure, but was only 11.0% following dark treatment. The total anthocyanin content was 7-fold higher in immature embryos cultured for 24 h under light conditions compared to embryos cultured in the dark. Transcriptome analysis revealed that the differentially expressed genes between immature embryos cultured for 24 h in dark and light chambers were significantly enriched in the pathways of flavonoid, flavone, flavonol and anthocyanin biosynthesis. Among the genes involved in anthocyanin biosynthesis, five up-regulated genes were identified: F3H, DFR, ANS, F3'H and the MYB transcription factor-encoding gene C1. The expression patterns of 14 selected genes were confirmed using quantitative reverse transcription-polymerase chain reaction. CONCLUSION: Light is the most important factor facilitating anthocyanin accumulation in immature embryos. After 24 h of exposure to light, the expression levels of the structural genes F3H, DFR, ANS, F3'H and transcription factor gene C1 were significantly up-regulated. This study provides new insight into the factors and key genes regulating anthocyanin biosynthesis in immature embryos, and supports improved efficiency of immature haploid embryo selection during doubled haploid breeding of maize.

Elevated Level of Cerebrospinal Fluid Pyruvate Dehydrogenase Kinase 4 Is a Predictive Biomarker of Clinical Outcome after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a central nervous system disease with high mortality and morbidity. Some independent factors valuable for prognosis prediction in patients with SAH are still lacking. In our earlier study, we found that PDK4 exerts a protective effect after SAH, primarily by reducing oxidative stress and neuronal death via the ROS/ASK1/p38 signaling pathway. Therefore, we investigated the changes in the level of pyruvate dehydrogenase kinase 4 (PDK4) in patients after subarachnoid hemorrhage (SAH) and analyzed the value of the cerebrospinal fluid (CSF) PDK4 level in predicting the prognoses of patients with SAH after interventional embolization surgery. Some knee arthritis subjects who needed surgery were recruited as a control group. The results showed that PDK4 expression was elevated in the CSF of SAH patients compared with that of controls. PDK4 levels in CSF (OR = 4.525; 95% CI: 1.135-18.038; p = 0.032), time to surgery (OR = 0.795; 95% CI: 0.646-0.977; p = 0.029), and initial GCS scores (OR = 2.758; 95% CI: 0.177-43.106; p = 0.469) were independent prognostic risk factors for SAH patients after surgery. The receiver operating characteristic (ROC) curve showed PDK4 levels in CSF had a higher predictive value. Thus, PDK4 in CSF could be an independent prognostic risk factor for SAH patients after surgery. PDK4 has the potential to serve as a new therapeutic target and biomarker for use in the diagnosis of SAH severity and the prediction of recovery.

Progress in the Clinical Assessment and Treatment of Myocardial Depression in Critically Ill Patient with Sepsis.

Myocardial inhibition is the main cause of death in patients with sepsis.In recent years, methodological differences in the diagnosis, assessment, and treatment of septic myocardial depression have been observed, and how to objectively and accurately evaluate the degree of myocardial depression and the timing of treatment strategies have generally been the focus of this area of research. Based on the relevant research at home and abroad, the current review summarizes the clinical characteristics, methodological diagnosis, and symptomatic treatment of septic myocardial depression. The aim of doing so is to provide a reference for the early identification and treatment of patients with sepsis and myocardial depression.

Alpha-Ketoglutarate Alleviates Neuronal Apoptosis Induced by Central Insulin Resistance through Inhibiting S6K1 Phosphorylation after Subarachnoid Hemorrhage.

Neuronal apoptosis after subarachnoid hemorrhage (SAH) is believed to play an important role in early brain injury after SAH. The energy metabolism of neuron is closely related to its survival. The transient hyperglycemia caused by insulin resistance (IR) after SAH seriously affects the prognosis of patients. However, the specific mechanisms of IR after SAH are still not clear. Studies have shown that α-KG takes part in the regulation of IR and cell apoptosis. In this study, we aim to investigate whether α-KG can reduce IR after SAH, improve the disorder of neuronal glucose metabolism, alleviate neuronal apoptosis, and ultimately play a neuroprotective role in SAH-induced EBI. We first measured α-KG levels in the cerebrospinal fluid (CSF) of patients with SAH. Then, we established a SAH model through hemoglobin (Hb) stimulation with HT22 cells for further mechanism research. Furthermore, an in vivo SAH model in mice was established by endovascular perforation. Our results showed that α-KG levels in CSF significantly increased in SAH patients and could be used as a potential prognostic biomarker. In in vitro model of SAH, we found that α-KG not only inhibited IR-induced reduction of glucose uptake in neurons after SAH but also alleviated SAH-induced neuronal apoptosis. Mechanistically, we found that α-KG inhibits neuronal IR by inhibiting S6K1 activation after SAH. Moreover, neuronal apoptosis significantly increased when glucose uptake was reduced. Furthermore, our results demonstrated that α-KG could also alleviate neuronal apoptosis in vivo SAH model. In conclusion, our study suggests that α-KG alleviates apoptosis by inhibiting IR induced by S6K1 activation after SAH.

Astrocytic CD24 Protects Neuron from Recombinant High-Mobility Group Box 1 Protein(rHMGB1)-Elicited Neuronal Injury.

Endogenous host-derived molecules named damage-associated molecular patterns (DAMPs) can induce excessive non-sterile inflammatory responses on recognition of specific membrane-tethered receptors. Here in this study, we aimed to explore the role of DAMP molecule HMGB1 in astrocyte-mediated sterile neuroinflammation and the resultant influences on neurons. In vitro cultured astrocytes were challenged with rHMGB1 and then harvested at 6 h, 12 h, 24 h, 36 h, and 48 h, respectively. The astrocytic CD24 expression was determined by quantitative real-time polymerase chain reaction (qPCR), Western blot analysis and immunofluorescence, nuclear factor kappa B (NF-κB) binding activity was detected by electrophoretic mobility shift assay (EMSA), and the proinflammatory factors, tumor necrosis factor-α (TNF-α), and interleukin 1ß (IL-1ß), were measured by qPCR. The neuronal morphology was assessed with phase-contrast microscopy. The results showed that astrocytic mRNA and protein CD24 expression began to rise at 24 h, peaked at 36 h, and remained elevated at 48 h after rHMGB1 stimulation, accompanied with enhanced NF-κB binding activity and augmented expression of TNF-α and IL-1ß. Furthermore, rHMGB1 caused cocultured neuron damage and was aggregated upon CD24 knockdown. Taken together, these novel findings suggested that rHMGB1 could promote astrocytic CD24 expression, the inhibition of which could aggregate neuronal damage.

High Expression of PDK4 Could Play a Potentially Protective Role by Attenuating Oxidative Stress after Subarachnoid Hemorrhage.

Pyruvate dehydrogenase (PDH), a key enzyme on the mitochondrial outer membrane, has been found to decrease activity notably in early brain injury (EBI) after subarachnoid hemorrhage (SAH). It has been demonstrated that PDH is associated with the production of reactive oxygen species (ROS) and apoptosis. Hence, in this study, we aimed to determine the cause of the decreased PDH activity and explore the potential role of PDH in EBI. We investigated the expression changes of PDH and pyruvate dehydrogenase kinase (PDK) in vivo and in vitro. Then, we explored the possible effects of PDH and ROS after SAH. The results showed that early overexpression of PDK4 promoted the phosphorylation of PDH, inhibited PDH activity, and may play a protective role after SAH in vivo and in vitro. Finally, we investigated the levels of PDK4 and pyruvate, which accumulated due to decreased PDH activity, in the cerebrospinal fluid (CSF) of 34 patients with SAH. Statistical analysis revealed that PDK4 and pyruvate expression was elevated in the CSF of SAH patients compared with that of controls, and this high expression correlated with the degree of neurological impairment and long-term outcome. Taken together, the results show that PDK4 has the potential to serve as a new therapeutic target and biomarker for assisting in the diagnosis of SAH severity and prediction of recovery.

Insulin resistance in ischemic stroke: Mechanisms and therapeutic approaches.

The pathological condition of insulin resistance prevents the neuroprotective effects of insulin. Numerous studies have demonstrated that insulin resistance, as an independent risk factor for ischemic stroke, accelerates the formation of thrombosis and promotes the development of atherosclerosis, both of which are major mechanisms of ischemic stroke. Additionally, insulin resistance negatively affects the prognosis of patients with ischemic stroke regardless of whether the patient has diabetes, but the mechanisms are not well studied. We explored the association between insulin resistance and the primary mechanisms of brain injury in ischemic stroke (inflammation, oxidative stress, and neuronal damage), looking for potential causes of poor prognosis in patients with ischemic stroke due to insulin resistance. Furthermore, we summarize insulin resistance therapeutic approaches to propose new therapeutic directions for clinically improving prognosis in patients with ischemic stroke.

A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice.

Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E2 (PGE2). PGE2 induction requires a nuclear factor κB-independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (TH1)/TH17 infiltration and aggravated colitis development. PGE2 administration ameliorated colitis in mouse models with defective PGE2 production but not in animals with normal PGE2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE2 biosynthesis, in inflamed tissues, and especially in colon Vimentin+Twist2+ stromal cells, in about 60% of patients with active Crohn's disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE2 production.

Transcatheter closure of muscular ventricular septal defects using the Cardi-O-Fix plug.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of the Cardi-O-Fix plug used for the treatment of muscular ventricular septal defects. METHODS: We retrospectively reviewed the medical records of five patients with muscular ventricular septal defects who underwent transcatheter closure using the Cardi-O-Fix Plug, from November 2017 to August 2019. The median age was 5.1 years (range: 3.2-6.5). Their median body weight was 18.1 kg (range: 13.4-21.8). All the patients underwent detailed two-dimensional Doppler and colour flow imaging by transthoracic echocardiography. The left ventricular median defect size of the muscular ventricular septal defects was 5.6 mm (range: 5.3-7.0). The right ventricular median defect size of the muscular ventricular septal defects was 3.9 mm (range: 3.3-4.7). All the procedures were performed on beating hearts. RESULTS: All the patients underwent successful device implantation with no displacement or detachment, they have complete echocardiographic closure at the 1-year follow-up. There were no occluder-related arrhythmia, chordae tendineae rupture, tricuspid insufficiency, aortic regurgitation, haemolysis, or embolisation. CONCLUSIONS: Application of the Cardi-O-Fix plug appears to be a feasible, safe, and effective treatment option for patients with muscular ventricular septal defects. Longer follow-up periods are warranted to prove the conclusion for long-term outcomes.