Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the "last patient in" date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23-0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08-0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Mitochondrial pyruvate carrier 2 mitigates acute kidney injury via sustaining mitochondrial metabolism.

Cisplatin, a chemotherapeutic drug, can result in acute kidney injury (AKI). Currently, there are no effective prevention methods. An incomplete understanding of the pathogenesis of AKI is a major barrier to the development of effective therapies. Metabolism reprogramming shift to glycolysis was involved in AKI pathogenesis. Glycolysis results in the pyruvate production. The mitochondrial pyruvate carrier (MPC) conveys cytosol pyruvate into mitochondria, promoting the tricarboxylic acid cycle. In this current study, we found a reduction in MPC2 expression in mice and cultured HK2 cells with cisplatin-induced AKI. MPC2 overexpression attenuated cisplatin-mediated nephrotoxicity both in vitro and in vivo via restoring pyruvate metabolism and mitochondrial function. Knockdown of MPC2 reversed this effect. Furthermore, artemether, an MPC2 potential activator, could mitigate AKI via regulating MPC2-mediated pyruvate metabolism. Our findings revealed that MPC2-pyruvate metabolism axis was a promising strategy to alleviate AKI induced by cisplatin.

Therapeutic effect of iridoid and xanthone glycosides components extracted from Swertia Mussotti on calculous cholecystitis and its clinical complications by targeting COX2.

Swertia Mussotti is used as febrifuge, analgesic and to treat calculous cholecystitis, however, the underling mechanism remains unclear. This study investigates the therapeutic effect of the active fraction named iridoid and xanthone glycoside (IXG) extracted from S. mussotii on six animal models related to calculous cholecystitis and its complications, and to explore its potential target proteins. Four main compounds including swertiamarin (STR), sweroside (SRS), gentiopicroside (GPS) and mangiferin (MGR) were identified from the IXG by UHPLC-TOF-MS. The in vivo experiments results confirmed that IXG significantly decreased the level of total bilirubin (TBIL), direct bilirubin (DBIL) and cyclooxygenase-2 (COX2) in calculous cholecystitis. IXG treatment dramatically reduced the number of twists and the time of clicking foot in 2nd phase induced by glacial acetic acid and formalin, however, no effect was showed on central pain established by hot plate test. IXG also significantly decreased the anal temperature induced by yeast and 2,4-dinitrophenol. These results indicated that IXG alleviate calculous cholecystitis and its clinical symptom. In addition, IXG suppressed the expression of Prostaglandin E2 (PGE2) in vitro. Mechanistically, COX2 was identified as the direct target of IXG in RAW264.7 cells, and downregulated the protein levels of COX2. The results confirmed that IXG ameliorates calculous cholecystitis and its clinical symptom (pain and fever) by suppressing the production of PGE2 through targeting COX2.

Individualized vaginal applicator for stage IIb primary vaginal adenocarcinoma: A case report.

BACKGROUND: Primary vaginal cancer is rare and most vaginal tumors are metastatic, often arising from adjacent gynecologic structures. Primary vaginal cancers are also more common among postmenopausal women and most of these are squamous cell carcinomas, with adenocarcinomas being relatively rare. Vaginal bleeding is the most common clinical manifestation of vaginal adenocarcinoma. About 70% of vaginal adenocarcinomas are stage I lesions at the time of diagnosis, for which radical surgery is recommended. However, more advanced vaginal cancers are not amenable to radical surgical treatment and have poor clinical outcomes. Optimal treatments modes are still being explored. Here, we report a rare case of stage IIb primary vaginal adenocarcinoma for which an individually designed vaginal applicator for after-loading radiotherapy was used to achieve good tumor control. CASE SUMMARY: A 62-year-old woman presented to our clinic after 3 months of abnormal postmenopausal vaginal bleeding. Gynecological examination, computed tomography (CT), and positron emission tomography-CT showed a large mass (about 5 cm) on the anterior vaginal wall. Colposcopy biopsy confirmed adenocarcinoma of vaginal origin. After three cycles of carboplatin plus paclitaxel chemotherapy, the lesion partially shrunk. The patient then received external irradiation of 45 gray (gy) in 25 fractions, which further reduced the vaginal lesion, followed by after-loading radiotherapy of 30 gy in 5 fractions with an individually designed vaginal applicator. Three months later, magnetic resonance imaging showed a slight thickening of the anterior vaginal wall. CONCLUSION: Primary vaginal adenocarcinoma is rare, and prognosis is poor in most vaginal cancers of locally advanced stages, which cannot be treated with radical surgery. Better tumor control can be achieved with an individualized vaginal applicator that allows administration of a higher radical dose to the tumor area while protecting normal tissues.

A comparative study of the relationship between time in range assessed by self-monitoring of blood glucose and continuous glucose monitoring with microalbuminuria outcome, HOMA-IR and HOMA-ß test.

AIMS: To compare the time in range (TIR) obtained from self-monitoring of blood glucose (SMBG) with that obtained from continuous glucose monitoring (CGM), and explore the relationship of TIR with microalbuminuria outcome, HOMA-IR and HOMA-ß test. METHODS: We recruited 400 patients with type 2 diabetes to carry out blood glucose monitoring by both SMBG and CGM for 3 consecutive days. TIR, TAR, TBR and other blood glucose variation indices were calculated respectively through the glucose data achieved from SMBG and CGM. The HOMA-IR and HOMA-ß test was evaluated by an oral glucose tolerance test. Urinary microalbumin-to-creatinine ratio completed in the laboratory. RESULTS: The median (25 %, 75 % quartile) of TIRCGM and TIRSMBG were 74.94(44.90, 88.04) and 70.83(46.88, 87.50) respectively, and there was no significant difference, p = 0.489; For every 1 % increase in TIRCGM, the risk of microalbuminuria decreased by 1.6 % (95%CI:0.973, 0.995, p = 0.006) and for every 1 % increase in TIRSMBG, the risk of microalbuminuria decreased by 1.3 % (95%CI:0.975, 0.999, p = 0.033). Stepwise multiple linear regression analysis showed an independent positive correlation between TIR (including TIRCGM and TIRSBMG) and LnDI30 and LnDI120 levels (p = 0.000). CONCLUSIONS: The TIR calculated by SMBG was highly consistent with that reported by CGM and was significantly associated with the risk of microalbuminuria and the HOMA-ß. Higher TIR quartiles were associated with lower incidence of microalbuminuria as well as higher lever of HOMA-ß. For patients with limited CGM application, SMBG-derived TIR may be an alternative to CGM-derived TIR, to assess blood glucose control.

Effect of Messaging on Support for Breast Cancer Screening Cessation Among Older US Women: A Randomized Clinical Trial.

Importance: Many older women are screened for breast cancer beyond guideline-recommended thresholds. Messaging holds promise to reduce overscreening. Objective: To investigate the effect of a message on older women's support for and intentions of stopping breast cancer screening. Design, Setting, and Participants: A 2-wave randomized clinical online survey trial using a nationally representative online panel was performed from May 12 to June 19, 2023. Women 65 years or older without breast cancer were eligible to participate. Intervention: A pilot-tested breast cancer screening cessation message delivered to a hypothetical older woman with serious illnesses and functional impairment. The message was described as from 1 of 3 sources (clinician, news story, or family member). Participants were randomized into 4 groups: no message (group 1 [control]), a single message from a clinician at wave 1 and no message at wave 2 (group 2), a message from a news story (wave 1) and a clinician (wave 2) (group 3), and a message from a family member (wave 1) and a clinician (wave 2) (group 4). Main Outcomes and Measures: Support for stopping screening in the hypothetical older woman (primary) and screening intentions for oneself (secondary) were assessed on 7-point scales, with higher values indicating stronger support for and intentions to stop screening. Means were compared using analysis of variance. The message effect on screening intentions among participants 75 years or older and those with life expectancy of less than 10 years were also explored. Results: A total of 3051 women participated in wave 1 of the trial. The mean (SD) age was 72.8 (5.9) years; 272 (8.9%) were non-Hispanic Black and 2506 (82.1%) were non-Hispanic White. Of these women, 2796 (91.6%) completed wave 2. Group 2 had significantly higher support for screening cessation in the hypothetical patient at wave 2 (mean score, 3.14 [95% CI, 2.99-3.29]) compared with group 1 (mean score, 2.68 [95% CI, 2.54-2.82]; P < .001). The effect was even stronger in group 3 (mean score, 4.23 [95% CI, 4.09-4.38]) and group 4 (mean score, 4.12 [95% CI, 3.97-4.27]) compared with both groups 1 and 2 (all P < .001). Message effects on self-screening intentions followed a similar pattern, with larger effects among participants 75 years or older or with limited life expectancy. Conclusions and Relevance: In this randomized clinical trial, a breast cancer screening cessation message significantly increased older women's support for and intentions of screening cessation. The strongest effects were observed when the message was delivered over time from multiple sources. Future work needs to engage potential message sources to examine the feasibility and acceptability of multilevel messaging strategies and their effect on screening behavior. Trial Registration: ClinicalTrials.gov Identifier: NCT05821023.

Combination of radiotherapy and PD-L1 blockade induces abscopal responses in EGFR-mutated lung cancer through activating CD8+ T cells.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+T cells was lower in EGFR-mutated NSCLC. In addition, CD8+T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.

Progress and Challenges of Topical Delivery Technologies Meditated Drug Therapy for Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease commonly seen in middle-aged and elderly people. Multiple cytokines are involved in the local tissue damage in OA. Currently, non-pharmacologic and surgical interventions are the main conventional approaches for the treatment of OA. In terms of pharmaceutical drug therapy, NSAIDs and acetaminophen are mainly used to treat OA. However, it is prone to various adverse reactions such as digestive tract ulcer, thromboembolism, prosthesis loosening, nerve injury and so on. With the in-depth study of OA, more and more novel topical drug delivery strategies and vehicles have been developed, which can make up for the shortcomings of traditional dosage forms, improve the bioavailability of drugs, and significantly reduce drug side effects. This review summarizes the immunopathogenesis, treatment guidelines, and progress and challenges of topical delivery technologies of OA, with some perspectives on the future pharmacological treatment of OA proposed.

Using olfactory cues in text materials benefits delayed retention and schemata construction.

Olfactory cues are considered a new sensory medium that can enhance learning, but the lack of empirical data has hampered their widespread use in educational practice. This requires empirical research to explore the effects of olfactory cues on learning. To address this research need, an experimental research study was conducted among 87 fourth graders from a Chinese elementary school. It explored the innovative design of adding olfactory cues to text materials by examining their effects on retention and schemata construction as learning outcomes, as well as their influence on learners' cognitive load and learning experience. In this between-subjects design experiment, the experimental group (n = 44) learned text materials with the introduction of olfactory cues, while the control group (n = 43) only learned text materials. After the learning activity, participants were asked to complete the questionnaires, immediate test, and delayed test. The results revealed that the usage of olfactory cues synchronized with text materials can enhance delayed retention, facilitate schemata construction, and improve learner experience without increasing cognitive load. This study confirms the potential of well-designed olfactory cues in educational practice and provides insights for designing and presenting multimedia learning resources.

Older women's perspectives on the ethics of persuasion in doctor-patient communication.

BACKGROUND: Public health campaigns have often used persuasive techniques to promote healthy behaviors but the use of persuasion by doctors is controversial. We sought to examine older women's perspectives. METHODS: We conducted semi-structured interviews with 20 community-dwelling older women from the Baltimore metropolitan area. We asked whether participants thought it was ethically appropriate for doctors to try to persuade patients and explored their rationales. We probed about commonly used persuasive techniques and two example decisional contexts-stopping mammograms and moving out of one's house after multiple falls. We used qualitative thematic analysis to code the transcripts and summarized results into major themes. RESULTS: We found mixed views on the ethical appropriateness of persuasion (theme 1); supporters of persuasion were motivated by the potential benefit to patients' health, whereas opponents thought patients should be the ultimate decision-makers. Perspectives depended on the persuasive technique (theme 2), where emotional appeals elicited the most negative reactions while use of facts and patient stories were viewed more positively. Perspectives also varied by the decisional context (theme 3), where higher severity and certainty of harm influenced participants to be more accepting of persuasion. Participants suggested alternative communication approaches to persuasion (theme 4) that emphasized respect for patients. CONCLUSIONS: Our findings suggest that the type of persuasive technique and the decisional context are important considerations in the ethical debate around the use of persuasion. Limiting the use of persuasion to high-stakes decisions and using facts and patient stories rather than emotional appeals are likely more acceptable.

Measuring sexual behavior stigma among cisgender men who have sex with men: an assessment of cross-country measurement invariance.

Objectives: Globally, cisgender men who have sex with men experience sexual stigma, but limited investigation of cross-population scale performance hinder comparisons. As measurement invariance is a necessary but seldom-established criterion of valid cross-cultural comparisons, we assessed invariance in scales of stigma related to sexual behavior across 9 countries. Methods: This secondary analysis used data collected from adult (mean age=29.6, standard deviation=12.5) cisgender men who have sex with men (n=8,669) in studies from 6 West African, 2 Southern African, and 1 North American country from 2012-2016. A common item set assessed 2 sexual behavior stigma domains. A sequential process was used to test the factor structure and measurement invariance, which included multigroup confirmatory factor analyses (CFA). Individual countries, items, living with HIV, and disclosure were explored as possible sources of noninvariance. Results: Goodness-of-fit statistics indicated adequate fit of the same 2-factor model in 7 of the 9 countries. The chi2 difference test comparing a constrained and unconstrained 7-country model in which loadings and thresholds were freely estimated was significant (p<0.001), indicating metric and scalar noninvariance, but removing the US provided evidence of invariance and freeing certain items led to a finding of partial invariance. Sexuality disclosure exhibited a direct relationship with select stigma items in several countries. Conclusions: Our findings point to the utility of the two stigma scale dimensions in making cross-country comparisons, but also to the necessity of assessing invariance with explicit attention to several factors including differential disclosure of sexuality across contexts to ensure valid comparisons.

Sustained frailty remission and dementia risk in older adults: A longitudinal study.

INTRODUCTION: Physical frailty is reversible, but little is known about the sustainability of frailty remission and its impact on dementia. METHODS: Data were derived from the National Health and Aging Trends Study (NHATS) (2011 to 2021). Physical frailty was assessed using the Fried frailty phenotype, and frailty transition patterns across three waves were defined. The relationship of sustained frailty remission with incident dementia was examined using Cox proportional regression, stratified by age and gender. RESULTS: Among 1931 participants, 348 (18.0%) were capable of sustained frailty remission. During the 8-year follow-up, 279 participants developed dementia. In a fully adjusted model, sustained remission was associated with a lower risk of dementia (hazard ratio = 0.66, 95% confidence interval = 0.47 to 0.93). The association was more pronounced among younger-old and male participants but not observed among their counterparts. DISCUSSION: Sustained frailty remission was associated with a reduced risk of developing dementia. Physical frailty could be an essential forewarning of dementia and a target for interventions. HIGHLIGHTS: We provided new insights into the natural progression of frailty and its impact on dementia risk using a nationally representative sample Sustained frailty remission reduced risk of incident dementia. Age and gender played a role in the frailty-dementia link, and thus individualized dementia risk screening is necessary. Physical frailty could be an essential forewarning of cognitive decline and an ideal target for interventions to prevent dementia.

Comparison between solid pseudopapillary neoplasms of the pancreas and pancreatic ductal adenocarcinoma with cystic changes using computed tomography.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPN) share similar imaging findings with pancreatic ductal adenocarcinoma with cystic changes (PDAC with cystic changes), which may result in unnecessary surgery. AIM: To investigate the value of computed tomography (CT) in differentiation of SPN from PDAC with cystic changes. METHODS: This study retrospectively analyzed the clinical and imaging findings of 32 patients diagnosed with SPN and 14 patients diagnosed with PDAC exhibiting cystic changes, confirmed through pathological diagnosis. Quantitative and qualitative analysis was performed, including assessment of age, sex, tumor size, shape, margin, density, enhancement pattern, CT values of tumors, CT contrast enhancement ratios, "floating cloud sign," calcification, main pancreatic duct dilatation, pancreatic atrophy, and peripancreatic invasion or distal metastasis. Multivariate logistic regression analysis was used to identify relevant features to differentiate between SPN and PDAC with cystic changes, and receiver operating characteristic curves were obtained to evaluate the diagnostic performance of each variable and their combination. RESULTS: When compared to PDAC with cystic changes, SPN had a lower age (32 years vs 64 years, P < 0.05) and a slightly larger size (5.41 cm vs 3.90 cm, P < 0.05). SPN had a higher frequency of "floating cloud sign" and peripancreatic invasion or distal metastasis than PDAC with cystic changes (both P < 0.05). No significant difference was found with respect to sex, tumor location, shape, margin, density, main pancreatic duct dilatation, calcification, pancreatic atrophy, enhancement pattern, CT values of tumors, or CT contrast enhancement ratios between the two groups (all P > 0.05). The area under the receiver operating characteristic curve of the combination was 0.833 (95% confidence interval: 0.708-0.957) with 78.6% sensitivity, 81.3% specificity, and 80.4% accuracy in differentiation of SPN from PDAC with cystic changes. CONCLUSION: A larger tumor size, "floating cloud sign," and peripancreatic invasion or distal metastasis are useful CT imaging features that are more common in SPN and may help discriminate SPN from PDAC with cystic changes.

Social life of free-living amoebae in aquatic environment- comprehensive insights into interactions of free-living amoebae with neighboring microorganisms.

Free-living amoebae (FLA) are prevalent in nature and man-made environments, and they can survive in harsh conditions by forming cysts. Studies have discovered that some FLA species are able to show pathogenicity to human health, leading to severe infections of central nervous systems, eyes, etc. with an extremely low rate of recovery. Therefore, it is imperative to establish a surveillance framework for FLA in environmental habitats. While many studies investigated the risks of independent FLA, interactions between FLA and surrounding microorganisms determined microbial communities in ecosystems and further largely influenced public health. Here we systematically discussed the interactions between FLA and different types of microorganisms and corresponding influences on behaviors and health risks of FLA in the environment. Specifically, bacteria, viruses, and eukaryotes can interact with FLA and cause either enhanced or inhibited effects on FLA infectivity, along with microorganism community changes. Therefore, considering the co-existence of FLA and other microorganisms in the environment is of great importance for reducing environmental health risks.

Plasmodium vivax serological exposure markers: PvMSP1-42-induced humoral and memory B-cell response generates long-lived antibodies.

Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to accelerate malaria elimination. To determine the dynamic profiles of SEMs in current and past P. vivax infections, we screened and selected 11 P. vivax proteins from 210 putative proteins using protein arrays, with a set of serum samples obtained from patients with acute P. vivax and documented past P. vivax infections. Then we used a murine protein immune model to initially investigate the humoral and memory B cell response involved in the generation of long-lived antibodies. We show that of the 11 proteins, especially C-terminal 42-kDa region of P. vivax merozoite surface protein 1 (PvMSP1-42) induced longer-lasting long-lived antibodies, as these antibodies were detected in individuals infected with P. vivax in the 1960-1970s who were not re-infected until 2012. In addition, we provide a potential mechanism for the maintenance of long-lived antibodies after the induction of PvMSP1-42. The results indicate that PvMSP1-42 induces more CD73+CD80+ memory B cells (MBCs) compared to P. vivax GPI-anchored micronemal antigen (PvGAMA), allowing IgG anti-PvMSP1-42 antibodies to be maintained for a long time.

The association between olfactory subdomains and frailty: A prospective case‒control study investigation.

BACKGROUND: Amidst the rise of frailty among a globally aging population, olfactory decline has emerged as a harbinger of frailty and mortality in population-level studies. However, the relationships between frailty and the olfactory subdomains of identification (OI), discrimination (OD), and threshold (OT) remain unexplored. This study prospectively examined the association between olfactory subdomains and the physical frailty phenotype (PFP) to investigate olfactory evaluation as a means of frailty screening. METHODS: A case‒control study of 45 frail and 45 non-frail individuals matched by age and sex. OT, OD, OI (range 0‒16), and composite sum (threshold, discrimination, and identification scores [TDI], range 0‒48) were measured with Sniffin' Sticks. PFP was defined by presence of three or more criteria: physical inactivity, self-reported exhaustion, muscle weakness, slow gait, and unintentional weight loss. Conditional logistic regression evaluated associations between olfactory subdomains and frailty. RESULTS: Ninety individuals with mean age of 83.1 ± 4.9 years, 60% female (n = 54), and 87.8% white (n = 79) were included. Olfactory scores were significantly lower in the frail group for OI (9.2 vs. 12.1, p < 0.001), OD (8.1 vs. 11.6, p < 0.001), OT (4.4 vs. 8.5, p < 0.001), and TDI (21.7 vs. 32.2, p < 0.001) than in the non-frail group. A single-point decrease in olfactory score was associated with increased odds of frailty in OT (odds ratio [OR]: 2.21, 95% confidence interval: [1.22, 3.98]), OD (OR: 2.19, 95% CI: [1.32, 3.65]), OI (OR: 2.29, 95% CI: [1.19, 4.39]), and TDI (OR: 1.54, 95% CI: [1.14, 2.08]). CONCLUSION: The robust association between olfactory subdomain scores and frailty suggests that olfaction may be an accessible signifier of frailty. Future studies should investigate this relationship longitudinally to assess predictive relationships.