Transdiagnostic and tailored internet intervention to improve mental health among university students: Research protocol for a randomized controlled trial.

BACKGROUND: Emerging adulthood is often associated with mental health problems. About one in three university students report symptoms of depression and anxiety that can negatively affect their developmental trajectory concerning work, intimate relationships, and health. This can interfere with academic performance, as mood and anxiety disorders are key predictors of dropout from higher education. A treatment gap exists, where a considerable proportion of students do not seek help for mood and anxiety symptoms. Offering internet interventions to students with mental health problems could reduce the treatment gap, increase mental health, and improve academic performance. A meta-analysis on internet interventions for university students showed small effects for depression and none for anxiety. Larger trials are recommended to further explore effects of guidance, transdiagnostic approaches, and individual treatment components. METHODS: This study will offer 1200 university students in Sweden participation in a three-armed randomized controlled trial (RCT) evaluating a guided or unguided transdiagnostic internet intervention for mild to moderate depression and anxiety, where the waitlist control group accesses the intervention at 6-month follow-up. Students reporting suicidal ideation/behaviors will be excluded and referred to treatment within the existing healthcare system. An embedded study within the trial (SWAT) will assess at week 3 of 8 whether participants in the guided and unguided groups are at higher risk of failing to benefit from treatment. Those at risk will be randomized to an adaptive treatment strategy, or to continue the treatment as originally randomized. Primary outcomes are symptoms of depression and anxiety. Follow-ups will occur at post-treatment and at 6-, 12-, and 24-month post-randomization. Between-group outcome analyses will be reported, and qualitative interviews about treatment experiences are planned. DISCUSSION: This study investigates the effects of a transdiagnostic internet intervention among university students in Sweden, with an adaptive treatment strategy employed during the course of treatment to minimize the risk of treatment failure. The study will contribute knowledge about longitudinal trajectories of mental health and well-being following treatment, taking into account possible gender differences in responsiveness to treatment. With time, effective internet interventions could make treatment for mental health issues more widely accessible to the student group.

Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs: an in vitro assessment.

BACKGROUND: It has become evident in the field of oncology that the outcome of medical treatment is influenced by the combined effect exerted on both cancer- and immune cells. Therefore, we evaluated potential immunological effects of 46 standard anticancer agents and 22 commonly administered concomitant non-cancer drugs. METHODS: We utilized a miniaturized in vitro model system comprised of fluorescently labeled human colon and lung cancer cell lines grown as monocultures and co-cultured with activated peripheral blood mononuclear cells (PBMCs). The Bliss Independence Model was then applied to detect antagonism and synergy between the drugs and activated immune cells. RESULTS: Among the standard anticancer agents, tyrosine kinase inhibitors (TKIs) stood out as the top inducers of both antagonism and synergy. Ruxolitinib and dasatinib emerged as the most notably antagonistic substances, exhibiting the lowest Bliss scores, whereas sorafenib was shown to synergize with activated PBMCs. Most concomitant drugs did not induce neither antagonism nor synergy. However, the statins mevastatin and simvastatin were uniquely shown to synergize with activated PBMC at all tested drug concentrations in the colon cancer model. CONCLUSION: We utilized a miniaturized tumor-immune model to enable time and cost-effective evaluation of a broad panel of drugs in an immuno-oncology setting in vitro. Using this approach, immunomodulatory effects exerted by TKIs and statins were identified.

Effects of COVID-19 contagion in cohabitants and family members on mental health and academic self-efficacy among university students in Sweden: a prospective longitudinal study.

OBJECTIVE: This study used causal inference to estimate the longitudinal effects of contagion in cohabitants and family members on university students' mental health and academic self-efficacy during the COVID-19 pandemic. DESIGN: A prospective longitudinal study including a baseline online measurement in May 2020, and online follow-ups after 5 months and 10 months. Participants were recruited through open-access online advertising. SETTING: Public universities and university colleges in Sweden. PARTICIPANTS: The analytical sample included 2796 students. OUTCOME MEASURES: Contagion in cohabitants and in family members was assessed at baseline and at the 5-month follow-up. Mental health and academic self-efficacy were assessed at the 5-month and 10-month follow-ups. RESULTS: Mild symptoms reported in cohabitants at baseline resulted in negative mental health effects at follow-up 5 months later, and mild baseline symptoms in family members resulted in negative effects on academic self-efficacy at follow-ups both 5 and 10 months later. CONCLUSIONS: Notwithstanding the lack of precision in estimated effects, the findings emphasise the importance of social relationships and the challenges of providing students with sufficient support in times of crisis.

Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening.

Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughput ex vivo drug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporates ex vivo treatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27 327 cells are freely available to extend to future scRNA-seq methodological comparisons.

A Cross-Cultural Comparison of Negative Alcohol-Related Consequences in the United States and Sweden: Measurement Invariance of the Rutgers Alcohol Problem Index.

Commensurate measures of alcohol-related consequences across countries and cultures are critical for addressing the global burden of hazardous alcohol use. The Rutgers Alcohol Problem Index (RAPI), developed and validated in the United States, is a popular measure of alcohol problems. This study examined measurement invariance of the RAPI across samples of U.S. and Swedish high school seniors. Latent mean differences in alcohol problems across countries and differences in associations between alcohol problems with alcohol use and protective behavioral strategies (PBS) were also examined. The RAPI was scalar invariant. Swedish students reported fewer problems than U.S. students (latent mean difference = -0.19, p = .047). In both samples, the RAPI was positively correlated with alcohol use frequency and quantity (ps < .001), and negatively correlated with PBS use (ps < .05). Overall, the RAPI demonstrated measurement invariance, and we found evidence for its validity across samples of U.S. and Swedish high school seniors.

Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death.

BACKGROUND: High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents. METHODS: We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death. RESULTS: The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model. CONCLUSION: Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.

The transition from animal to human culture-simulating the social protocell hypothesis.

The origin of human cumulative culture is commonly envisioned as the appearance (some 2.0-2.5 million years ago) of a capacity to faithfully copy the know-how that underpins socially learned traditions. While certainly plausible, this story faces a steep 'startup problem'. For example, it presumes that ape-like early Homo possessed specialized cognitive capabilities for faithful know-how copying and that early toolmaking actually required such a capacity. The social protocell hypothesis provides a leaner story, where cumulative culture may have originated even earlier-as cumulative systems of non-cumulative traditions ('institutions' and 'cultural lifestyles'), via an emergent group-level channel of cultural inheritance. This channel emerges as a side-effect of a specific but in itself unremarkable suite of social group behaviours. It is independent of faithful know-how copying, and an ancestral version is argued to persist in Pan today. Hominin cultural lifestyles would thereby have gained in complexity and sophistication, eventually becoming independent units of selection (socionts) via a cultural evolutionary transition in individuality, abstractly similar to the origin of early cells. We here explore this hypothesis by simulating its basic premises. The model produces the expected behaviour and reveals several additional and non-trivial phenomena as fodder for future work. This article is part of the theme issue 'Human socio-cultural evolution in light of evolutionary transitions'.

A longitudinal study on the impact of Internet gaming disorder on self-perceived health, academic performance, and social life of first-year college students.

BACKGROUND AND OBJECTIVES: Internet gaming disorder (IGD) is associated with health, social, and academic problems but whether these are consequences of the disorder rather than precursors or correlates is unclear. We aimed to evaluate whether IGD in the 1st year of university predicts health, academic and social problems 1 year later, controlling for baseline health, academic and social problems, demographics, and mental health symptoms. METHODS: In a prospective cohort study, 1741 university students completed both a baseline online survey in their 1st year and a follow-up survey 1 year later. Log-binomial models examined the strength of prospective associations between baseline predictor variables (IGD, baseline health, academic and social problems, sex, age, and mental health symptoms) and occurrence of health, academic and social problems at follow-up. RESULTS: When extensively adjusted by the corresponding outcome at baseline, any mental disorder symptoms, sex, and age, baseline IGD was associated only with severe school impairment and poor social life (risk ratio [RR] = 1.77; 95% confidence interval [CI] = 1.14-2.75, p = .011; RR = 1.22; 95% CI = 1.07-1.38, p = .002, respectively). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: University authorities and counselors should consider that incoming 1st-year students that meet criteria for IGD are likely to have increased academic and social impairments during their 1st year for which they may want to intervene. This study adds to the existing literature by longitudinally examining a greater array of negative outcomes of IGD than previously documented.

Validation of the Alcohol-Related Sexual Consequences Scale in Swedish University Students.

BACKGROUND: Alcohol-related sexual consequences are common in college students. A newly developed 41-item Alcohol-Related Sexual Consequences Scale has recently been evaluated in at-risk young adults in the U.S. The current study aims to validate the Scale in Swedish college students. METHODS: The occurrence of alcohol-related sexual consequences was assessed by birth gender, relationship status, gender identity/sexual orientation, and age. Negative binomial regression was used to assess convergent and divergent validity. RESULTS: On average, 5.4 (SD 5.1) alcohol-related sexual consequences were experienced past three months. Greater scores were reported in singles, LGBTQ (Lesbian, Gay, Bisexual, Transgender, Queer/Questioning), and younger students. All sex-related covariates showed robust associations with alcohol-related sexual consequences while most alcohol-related covariates were not associated (e.g., convergent validity). All alcohol-related covariates showed robust associations with alcohol consequences while most sex-related covariates were not associated (e.g., divergent validity). In the full model predicting alcohol-related sexual consequences, being a woman, single, and younger were identified as independent predictors. CONCLUSIONS: This newly developed scale assessing alcohol-related sexual consequences could be used in both epidemiological studies and intervention studies targeting at-risk students.

Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients.

Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as 'concomitant drugs', have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.

Academic self-efficacy: Associations with self-reported COVID-19 symptoms, mental health, and trust in universities' management of the pandemic-induced university lockdown.

Objective: To investigate perceived changes in academic self-efficacy associated with self-reported symptoms of COVID-19, changes in mental health, and trust in universities' management of the pandemic and transition to remote education during lockdown of Swedish universities in the spring of 2020. Methods: 4495 participated and 3638 responded to self-efficacy questions. Associations were investigated using multinomial regression. Results: Most students reported self-experienced effects on self-efficacy. Lowered self-efficacy was associated with symptoms of contagion, perceived worsening of mental health and low trust in universities' capacity to successfully manage the lockdown and transition to emergency remote education. Increased self-efficacy was associated with better perceived mental health and high trust in universities. Conclusion: The initial phase of the pandemic was associated with a larger proportion of students reporting self-experienced negative effects on academic self-efficacy. Since self-efficacy is a predictor of academic performance, it is likely that students' academic performance will be adversely affected.

Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome.

Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short­term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross­resistance and association with progression­free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment­naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross­resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.

Single-cell transcriptional pharmacodynamics of trifluridine in a tumor-immune model.

Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.

Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma.

Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.

Symptoms of COVID-19 contagion in different social contexts in association to self-reported symptoms, mental health and study capacity in Swedish university students.

OBJECTIVE: The present study investigates if symptoms of COVID-19 contagion in different social contexts (cohabitants, family, acquaintances, and others) are associated with university students' own self-reported symptoms of COVID-19 contagion, mental health, and study capacity. This was investigated by a cross-sectional survey administrated in Sweden during the first wave of the COVID-19 pandemic, at the time when universities were locked down to limit viral spread and contagion. RESULTS: Mild to moderate symptoms of COVID-19 in cohabitants and family members were associated with student's self-reported symptoms of contagion, while no associations could be seen in relation to mental health and study capacity. Symptoms of COVID-19 contagion in acquaintances and others were not associated with students' self-reported symptoms, nor with their mental health and study capacity. To conclude, during the initial lockdown of universities students' self-reported symptoms of contagion were mainly associated with cohabitants and family members, while symptoms of contagion in different social contexts were not associated with mental health and study capacity. Findings suggest that lockdown of universities may have contributed to limiting infection pathways, while still allowing students to focus on their studies despite significant contagion among others known to the student.

Compliance with recommendations limiting COVID-19 contagion among university students in Sweden: associations with self-reported symptoms, mental health and academic self-efficacy.

AIMS: The COVID-19 containment strategy in Sweden uses public health recommendations relying on personal responsibility for compliance. Universities were one of few public institutions subject to strict closure, meaning that students had to adapt overnight to online teaching. This study investigates the prevalence of self-reported recommendation compliance and associations with self-reported symptoms of contagion, self-experienced effects on mental health and academic self-efficacy among university students in Sweden in May-June 2020. METHODS: This was a cross-sectional 23 question online survey in which data were analysed by multinomial regression, taking a Bayesian analysis approach complemented by null hypothesis testing. RESULTS: A total of 4495 students consented to respond. Recommendation compliance ranged between 70% and 96%. Women and older students reported higher compliance than did men and younger students. Mild to moderate COVID-19 symptoms were reported by 30%, severe symptoms by fewer than 2%; 15% reported being uncertain and half of the participants reported no symptoms. Mental health effects were reported by over 80%, and changes in academic self-efficacy were reported by over 85%; in both these areas negative effects predominated. Self-reported symptoms and uncertainty about contagion were associated with non-compliance, negative mental health effects, and impaired academic self-efficacy. CONCLUSIONS: Students generally followed public health recommendations during strict closure of universities, but many reported considerable negative consequences related to mental health and academic self-efficacy. Digital interventions should be developed and evaluated to boost coping skills, build resilience and alleviate student suffering during the pandemic and future similar crises.

Associations between Risk Factors in Late Adolescence and Problem Behaviors in Young Adulthood: A Six-Year Follow-Up of Substance Related and Behavioral Addictions in Swedish High School Seniors.

INTRODUCTION: Risk factors of traditional substance use related problems in young adults are more well-known than for behavioral addictions such as gambling and gaming problems. The present study aims to provide knowledge about the longitudinal patters of substance use related and behavioral addictions in early adulthood. METHODS: Using self-report surveys, substance-related, psychiatric, and demographic predictors were assessed in Swedish high school seniors and re-assessed six years later along with gambling and gaming problems, n = 800. Associations (Risk Ratios) between risk factors in late adolescence and problem behaviors in young adulthood were analyzed. RESULTS: Tobacco use, illicit drug use, and hazardous drinking in young adulthood were associated with tobacco use, illicit drug use, alcohol use, conduct problems, and impaired impulse control in late adolescence. Gambling problems in young adulthood were only associated with heredity of alcohol problems, while gaming was not associated to any problem behavior in late adolescence. CONCLUSION: It is concluded that predictors for traditional substance-related addictions differ from predictors for behavioral addictions, and that this difference is more pronounced for gaming problems than for gambling problems.

Associations between compliance with covid-19 public health recommendations and perceived contagion in others: a self-report study in Swedish university students.

OBJECTIVE: During the COVID pandemic, government authorities worldwide have tried to limit the spread of the virus. Sweden's distinctive feature was the use of voluntary public health recommendations. Few studies have evaluated the effectiveness of this strategy. Based on data collected in the spring of 2020, this study explored associations between compliance with recommendations and observed symptoms of contagion in others, using self-report data from university students. RESULTS: Compliance with recommendations ranged between 69.7 and 95.7 percent. Observations of moderate symptoms of contagion in "Someone else I have had contact with" and "Another person" were markedly associated with reported self-quarantine, which is the most restrictive recommendation, complied with by 81.2% of participants. Uncertainty regarding the incidence and severity of contagion in cohabitants was markedly associated with the recommendation to avoid public transportation, a recommendation being followed by 69.7%. It is concluded that students largely followed the voluntary recommendations implemented in Sweden, suggesting that coercive measures were not necessary. Compliance with recommendations were associated with the symptoms students saw in others, and with the perceived risk of contagion in the student's immediate vicinity. It is recommended that voluntary recommendations should stress personal relevance, and that close relatives are at risk.

Modeling the emergence of affective polarization in the social media society.

Rising political polarization in recent decades has hampered and gridlocked policymaking, as well as weakened trust in democratic institutions. These developments have been linked to the idea that new media technology fosters extreme views and political conflict by facilitating self-segregation into "echo chambers" where opinions are isolated and reinforced. This opinion-centered picture has recently been challenged by an emerging political science literature on "affective polarization", which suggests that current polarization is better understood as driven by partisanship emerging as a strong social identity. Through this lens, politics has become a question of competing social groups rather than differences in policy position. Contrary to the opinion-centered view, this identity-centered perspective has not been subject to dynamical formal modeling, which generally permits hypotheses about micro-level explanations for macro-level phenomena to be systematically tested and explored. We here propose a formal model that links new information technology to affective polarization via social psychological mechanisms of social identity. Our results suggest that new information technology catalyzes affective polarization by lowering search and interaction costs, which shifts the balance between centrifugal and centripetal forces of social identity. We find that the macro-dynamics of social identity is characterized by two stable regimes on the societal level: one fluid regime, in which identities are weak and social connections heterogeneous, and one solid regime in which identities are strong and groups homogeneous. We also find evidence of hysteresis, meaning that a transition into a fragmented state is not readily reversed by again increasing those costs. This suggests that, due to systemic feedback effects, if polarization passes certain tipping points, we may experience run-away political polarization that is highly difficult to reverse.