Mountaintop Removal Coal Mining Contaminates Snowpack across a Broad Region.

Mountaintop removal coal mining is a source of downstream pollution. Here, we show that mountaintop removal coal mining also pollutes ecosystems downwind. We sampled regional snowpack near the end of winter along a transect of sites located 3-60 km downwind of coal mining in the Elk River valley of British Columbia, Canada. Vast quantities of polycyclic aromatic compounds (PACs), a toxic class of organic contaminants, are emitted and transported atmospherically far from emission sources. Summed PAC (ΣPAC) snowpack concentrations ranged from 29-94,866 ng/L. Snowpack ΣPAC loads, which account for variable snowpack depth, ranged from <10 µg/m2 at sites >50 km southeast of the mines to >1000 µg/m2 at sites in the Elk River valley near mining operations, with one site >15,000 µg/m2. Outside of the Elk River valley, snowpack ΣPAC loads exhibited a clear spatial pattern decreasing away from the mines. The compositional fingerprint of this PAC pollution matches closely with Elk River valley coal. Beyond our study region, modeling results suggest a depositional footprint extending across western Canada and the northwestern United States. These findings carry important implications for receiving ecosystems and for communities located close to mountaintop removal coal mines exposed to air pollution elevated in PACs.

Exploring Anesthesia Provider Preferences for Precision Feedback: Preference Elicitation Study.

Background: Health care professionals must learn continuously as a core part of their work. As the rate of knowledge production in biomedicine increases, better support for health care professionals' continuous learning is needed. In health systems, feedback is pervasive and is widely considered to be essential for learning that drives improvement. Clinical quality dashboards are one widely deployed approach to delivering feedback, but engagement with these systems is commonly low, reflecting a limited understanding of how to improve the effectiveness of feedback about health care. When coaches and facilitators deliver feedback for improving performance, they aim to be responsive to the recipient's motivations, information needs, and preferences. However, such functionality is largely missing from dashboards and feedback reports. Precision feedback is the delivery of high-value, motivating performance information that is prioritized based on its motivational potential for a specific recipient, including their needs and preferences. Anesthesia care offers a clinical domain with high-quality performance data and an abundance of evidence-based quality metrics. Objective: The objective of this study is to explore anesthesia provider preferences for precision feedback. Methods: We developed a test set of precision feedback messages with balanced characteristics across 4 performance scenarios. We created an experimental design to expose participants to contrasting message versions. We recruited anesthesia providers and elicited their preferences through analysis of the content of preferred messages. Participants additionally rated their perceived benefit of preferred messages to clinical practice on a 5-point Likert scale. Results: We elicited preferences and feedback message benefit ratings from 35 participants. Preferences were diverse across participants but largely consistent within participants. Participants' preferences were consistent for message temporality (α=.85) and display format (α=.80). Ratings of participants' perceived benefit to clinical practice of preferred messages were high (mean rating 4.27, SD 0.77). Conclusions: Health care professionals exhibited diverse yet internally consistent preferences for precision feedback across a set of performance scenarios, while also giving messages high ratings of perceived benefit. A "one-size-fits-most approach" to performance feedback delivery would not appear to satisfy these preferences. Precision feedback systems may hold potential to improve support for health care professionals' continuous learning by accommodating feedback preferences.

Combined regenerative rehabilitation improves recovery following volumetric muscle loss injury in a rat model.

Volumetric muscle loss (VML) injury causes irreversible deficits in muscle mass and function, often resulting in permanent disability. The current standard of care is physical therapy, but it is limited in mitigating functional deficits. We have previously optimized a rehabilitation technique using electrically stimulated eccentric contraction training (EST) that improved muscle mass, strength, and size in VML-injured rats. A biosponge scaffold composed of extracellular matrix proteins has previously enhanced muscle function postVML. This study aimed to determine whether combining a regenerative therapy (i.e., biosponge) with a novel rehabilitation technique (i.e., EST) could enhance recovery in a rat model of VML. A VML defect was created by removing ~20% of muscle mass from the tibialis anterior muscle in adult male Lewis rats. Experimental groups included VML-injured rats treated with biosponge with EST or biosponge alone (n = 6/group). EST was implemented 2 weeks postinjury at 150 Hz and was continued for 4 weeks. A linear increase in eccentric torque over 4 weeks showed the adaptability of the VML-injured muscle to EST. Combining biosponge with EST improved peak isometric torque by ~52% compared with biosponge treatment alone at 6 weeks postinjury. Application of EST increased MyoD gene expression and the percentage of large (>2000 µm2) type 2B myofibers but reduced fibrotic tissue deposition in VML-injured muscles. Together, these changes may provide the basis for improved torque production. This study demonstrates the potential for combined regenerative and rehabilitative therapy to improve muscle recovery following VML.

Effects of protected area coverage and research on conservation status of primates globally.

Conducting conservation research and establishing protected areas (PAs) based on research results are critical to biodiversity conservation. However, the effect of research and PAs on conservation of threatened species has rarely been evaluated simultaneously. We collected data on PAs from 2000 for 2021 and determined the number of publications on global primates (published from 1950 to 2021) to assess the effect of PAs, research, and biological and socioeconomic factors on the current International Union for Conservation of Nature endangered status and change in status. We used the MCMCglmm package to conduct a phylogenetic comparative analysis to control the phylogenetic relationship of primate species. The status of 24.6% (82 of 333) of species assessed at least twice declined. Only the black lion tamarin (Leontopithecus chrysopygus) had an improved status. Species with status declines mostly occurred on the south coast of West Africa and in Madagascar. PAs covered 22.1% of each species' range. Forest loss in PAs (5.5%) was significantly lower than forest loss within 5 km outside PAs (13.8%), suggesting PAs effectively mitigated forest loss. Both the median number of total publications and conservation publications on critically endangered species were higher than those of other categories. Models showed that PA coverage and number of publications or conservation-focused publications were not related to current status or change in status over time. A decline in status was not related to creation of PAs or increase of research since the last assessment. Our results suggest that current PAs and research are not reversing the extinction crisis of global primates. Doing more conservation-oriented research, strengthening management of current PAs, and expanding PAs will be needed to protect primates globally.

Efectos de la cobertura e investigación de áreas protegidas sobre el estado de conservación de los primates a nivel mundial Resumen La investigación para la conservación y la creación de áreas protegidas (AP) con base en sus resultados son de suma importancia para conservar la biodiversidad. Sin embargo, pocas veces se ha analizado de forma simultánea el efecto de la investigación y las AP sobre la conservación de especies amenazadas. Recolectamos datos sobre las AP entre el 2000 y el 2021 y determinamos el número de artículos sobre primates publicados entre 1950 y 2021 para evaluar el efecto de las AP, la investigación y los factores biológicos y socioeconómicos sobre el estado actual de en peligro y de cambio de estatus de la Unión Internacional para la Conservación de la Naturaleza. Usamos el paquete MCMCglmm para realizar un estudio filogenético comparativo para analizar la relación filogenética del estado de las especies y del cambio de estatus de primates. El estatus del 24.6% (82 de 333) de las especies analizadas declinó al menos dos veces. Solamente el tití leoncito (Leontopithecus chrysopygus) tuvo una mejoraría en su estado. Las especies con declinación en su estado se ubicaron principalmente en la costa sur del Oeste de África y en Madagascar. Las AP cubrieron el 22.1% de la distribución de cada especie. La pérdida de bosques en las AP (5.5%) fue mucho menor que la pérdida dentro de los primeros 5 km fuera de las AP (13.8%), lo que sugiere que las AP mitigan eficientemente la pérdida de bosque. Tanto el número medio de publicaciones totales como el de publicaciones sobre la conservación de especies en peligro crítico fue mayor que aquellos de cualquier otra categoría. Los modelos mostraron que la cobertura de AP y el número de publicaciones o de publicaciones enfocadas en la conservación no estaban relacionados con el estado actual o el cambio de estado. La declinación del estado no estuvo relacionada con la creación de AP o el incremento en la investigación desde nuestro último análisis. Nuestros resultados sugieren que la investigación y las AP actuales no están revirtiendo la crisis mundial de extinción de primates. Para proteger a los primates se necesitará realizar más investigación orientada a la conservación, fortalecer el manejo actual de las AP, así como expandirlas.

Associations between obesity, a composite risk score for probable long COVID, and sleep problems in SARS-CoV-2 vaccinated individuals.

BACKGROUND: Preliminary data suggests that obesity might hasten the decline in mRNA vaccine-induced immunity against SARS-CoV-2. However, whether this renders individuals with obesity more susceptible to long COVID symptoms post-vaccination remains uncertain. Given sleep's critical role in immunity, exploring the associations between obesity, probable long COVID symptoms, and sleep disturbances is essential. METHODS: We analyzed data from a survey of 5919 adults aged 18 to 89, all of whom received two SARS-CoV-2 mRNA vaccinations. Participants were categorized into normal weight, overweight, and obesity groups based on ethnicity-specific BMI cutoffs. The probability of long COVID was evaluated using the Post-Acute Sequelae of SARS-CoV-2 (PASC) score, as our survey did not permit confirmation of acute SARS-CoV-2 infection through methods such as antibody testing. Additionally, sleep patterns were assessed through questionnaires. RESULTS: Participants with obesity exhibited a significantly higher adjusted odds ratio (OR) of having a PASC score of 12 or higher, indicative of probable long COVID in our study, compared to those with normal weight (OR: 1.55, 95% CI: 1.05, 2.28). No significant difference was observed for overweight individuals (OR: 0.92 [95% CI: 0.63, 1.33]). Both obesity and probable long COVID were associated with increased odds of experiencing a heightened sleep burden, such as the presence of obstructive sleep apnea or insomnia (P < 0.001). However, no significant interaction between BMI and probable long COVID status was found. CONCLUSIONS: Even post-vaccination, individuals with obesity may encounter a heightened risk of experiencing prolonged COVID-19 symptoms. However, confirming our observations necessitates comprehensive studies incorporating rigorous COVID infection testing, such as antibody assays - unavailable in our anonymous survey. Additionally, it is noteworthy that the correlation between probable long COVID and sleep disturbances appears to be independent of BMI.

Neural indices of heritable impulsivity: Impact of the COMT Val158Met polymorphism on frontal beta power during early motor preparation.

Studies of COMT Val158Met suggest that the neural circuitry subserving inhibitory control may be modulated by this functional polymorphism altering cortical dopamine availability, thus giving rise to heritable differences in behaviors. Using an anatomically-constrained magnetoencephalography method and stratifying the sample by COMT genotype, from a larger sample of 153 subjects, we examined the spatial and temporal dynamics of beta oscillations during motor execution and inhibition in 21 healthy Met158/Met158 (high dopamine) or 21 Val158/Val158 (low dopamine) genotype individuals during a Go/NoGo paradigm. While task performance was unaffected, Met158 homozygotes demonstrated an overall increase in beta power across regions essential for inhibitory control during early motor preparation (∼100 ms latency), suggestive of a global motor "pause" on behavior. This increase was especially evident on Go trials with slow response speed and was absent during inhibition failures. Such a pause could underlie the tendency of Met158 allele carriers to be more cautious and inhibited. In contrast, Val158 homozygotes exhibited a beta drop during early motor preparation, indicative of high response readiness. This decrease was associated with measures of behavioral disinhibition and consistent with greater extraversion and impulsivity observed in Val homozygotes. These results provide mechanistic insight into genetically-determined interindividual differences of inhibitory control with higher cortical dopamine associated with momentary response hesitation, and lower dopamine leading to motor impulsivity.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.

Directed conservation of the world's reef sharks and rays.

Many shark populations are in decline around the world, with severe ecological and economic consequences. Fisheries management and marine protected areas (MPAs) have both been heralded as solutions. However, the effectiveness of MPAs alone is questionable, particularly for globally threatened sharks and rays ('elasmobranchs'), with little known about how fisheries management and MPAs interact to conserve these species. Here we use a dedicated global survey of coral reef elasmobranchs to assess 66 fully protected areas embedded within a range of fisheries management regimes across 36 countries. We show that conservation benefits were primarily for reef-associated sharks, which were twice as abundant in fully protected areas compared with areas open to fishing. Conservation benefits were greatest in large protected areas that incorporate distinct reefs. However, the same benefits were not evident for rays or wide-ranging sharks that are both economically and ecologically important while also threatened with extinction. We show that conservation benefits from fully protected areas are close to doubled when embedded within areas of effective fisheries management, highlighting the importance of a mixed management approach of both effective fisheries management and well-designed fully protected areas to conserve tropical elasmobranch assemblages globally.

Suicide Prevention by Peers Offering Recovery Tactics (SUPPORT) for US Veterans With Serious Mental Illness: Community Engagement Approach.

BACKGROUND: Peer specialists are hired, trained, and accredited to share their lived experience of psychiatric illness to support other similar individuals through the recovery process. There are limited data on the role of peer specialists in suicide prevention, including their role in intervention development. OBJECTIVE: To better understand peer specialists within the Veterans Health Administration (VHA), we followed partnership community engagement and a formative research approach to intervention development to (1) identify barriers, facilitators, and perceptions of VHA peer specialists delivering a suicide prevention service and (2) develop and refine an intervention curriculum based on an evidence-informed preliminary intervention framework for veterans with serious mental illness (SMI). METHODS: Following the community engagement approach, VHA local and national peer support and mental health leaders, veterans with SMI, and veteran peer specialists met to develop a preliminary intervention framework. Next, VHA peer specialist advisors (n=5) and scientific advisors (n=6) participated in respective advisory boards and met every 2-4 months for more than 18 months via videoconferencing to address study objectives. The process used was a reflexive thematic analysis after each advisory board meeting. RESULTS: The themes discussed included (1) the desire for suicide prevention training for peer specialists, (2) determining the role of VHA peer specialists in suicide prevention, (3) integration of recovery themes in suicide prevention, and (4) difficulties using safety plans during a crisis. There were no discrepancies in thematic content between advisory boards. Advisor input led to the development of Suicide Prevention by Peers Offering Recovery Tactics (SUPPORT). SUPPORT includes training in general suicide prevention and a peer specialist-delivered intervention for veterans with SMI at an increased suicide risk. This training aims to increase the competence and confidence of peer specialists in suicide prevention and the intervention supports veterans with SMI at an increased suicide risk through their recovery process. CONCLUSIONS: This paper intends to document the procedures taken in suicide prevention intervention development, specifically those led by peer specialists, and to be a source for future research developing and evaluating similar interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05537376; https://classic.clinicaltrials.gov/ct2/show/NCT05537376.

Heat-induced structural and chemical changes to a computationally designed miniprotein.

The de novo design of miniprotein inhibitors has recently emerged as a new technology to create proteins that bind with high affinity to specific therapeutic targets. Their size, ease of expression, and apparent high stability makes them excellent candidates for a new class of protein drugs. However, beyond circular dichroism melts and hydrogen/deuterium exchange experiments, little is known about their dynamics, especially at the elevated temperatures they seemingly tolerate quite well. To address that and gain insight for future designs, we have focused on identifying unintended and previously overlooked heat-induced structural and chemical changes in a particularly stable model miniprotein, EHEE_rd2_0005. Nuclear magnetic resonance (NMR) studies suggest the presence of dynamics on multiple time and temperature scales. Transiently elevating the temperature results in spontaneous chemical deamidation visible in the NMR spectra, which we validate using both capillary electrophoresis and mass spectrometry (MS) experiments. High temperatures also result in greatly accelerated intrinsic rates of hydrogen exchange and signal loss in NMR heteronuclear single quantum coherence spectra from local unfolding. These losses are in excellent agreement with both room temperature hydrogen exchange experiments and hydrogen bond disruption in replica exchange molecular dynamics simulations. Our analysis reveals important principles for future miniprotein designs and the potential for high stability to result in long-lived alternate conformational states.

Disparities in positive mental health of sexual and gender minority adults in Canada. / Disparités dans la santé mentale positive des adultes faisant partie d'une minorité sexuelle ou de genre au Canada.

INTRODUCTION: The goal of this study was to examine potential disparities in positive mental health (PMH) among adults in Canada by sexual orientation and gender modality. METHODS: Using 2019 Canadian Community Health Survey (CCHS) Annual Component data (N = 57 034), we compared mean life satisfaction and the prevalence of high self-rated mental health (SRMH), happiness and community belonging between heterosexual and sexual minority adults, and between cisgender and gender minority adults. We used 2019 CCHS Rapid Response on PMH data (N = 11 486) to compare the prevalence of high psychological well-being between heterosexual and sexual minority adults. Linear and logistic regression analyses examined the between-group differences in mean life satisfaction and the other PMH outcomes, respectively. RESULTS: Sexual minority (vs. heterosexual) adults reported lower mean life satisfaction (B = -0.7, 95% CI: -0.8, -0.5) and were less likely to report high SRMH (OR = 0.4, 95% CI: 0.3, 0.5), happiness (OR = 0.4, 95% CI: 0.3, 0.5), community belonging (OR = 0.6, 95% CI: 0.5, 0.7) and psychological well-being (OR = 0.4, 95% CI: 0.3, 0.6). Differences were not always significant for specific sexual minority groups in sexstratified analyses. Gender minority adults reported lower mean life satisfaction and were less likely to report high SRMH and happiness than cisgender adults. CONCLUSION: Future research could investigate how these PMH disparities arise, risk and protective factors in these populations, how other sociodemographic factors interact with sexual orientation and gender identity to influence PMH and changes in disparities over time.

Cognition and Functional Capacity: An Initial Comparison of Veteran and Non-Veteran Older Adults.

INTRODUCTION: The U.S. Military Veterans aged 65 and older comprise an estimated 43% of the 22 million living Veterans in the United States. Veterans have high rates of physical, psychiatric, and social challenges, but it is not known whether Veteran status confers additional risk for cognitive or functional impairments in later life. Thus, this investigation specifically compared older Veterans with their non-Veteran peers in cognitive functioning and performance-based functional capacity. MATERIALS AND METHODS: Participants (N = 110; 29 Veterans and 81 non-Veterans) were part of a larger longitudinal study on biopsychosocial functioning in independently living older adult residents of a Continuing Care Senior Housing Community. The University of California San Diego Institutional Review Board approved the study and all participants provided written informed consent. Participants provided demographic and mental health information and were administered a comprehensive neuropsychological battery. Functional capacity was assessed using the UCSD Performance-Based Skills Assessment-Brief (UPSA-B), which uses financial and communication role-plays to assess everyday functioning skills. Neuropsychological scores were appropriately normed prior to analysis. Multivariate Analyses of Variances with post hoc t-tests and an Analysis of Covariance were used to examine neuropsychological and functional capacity differences, respectively, between Veterans and non-Veterans. RESULTS: Veterans did not differ from non-Veterans in educational attainment (16.4 years versus 15.5 years, P = 0.110), but they were significantly older (mean age 86.9 years ± 5.7, versus 81.74 years ± 6.53; P < 0.001) and were more likely to be male (X2 [1, N = 110] = 62.39, P < 0.001). Thus, though neuropsychological norms already accounted for demographic differences in our participants, age and sex were controlled in the Analysis of Covariance predicting UPSA-B score from Veteran status. Results suggested that, compared to non-Veterans, Veterans had significantly worse performance in the list learning portion of a test of verbal memory (Hopkins Verbal Learning Test-Revised, Total Recall; t = 2.56, P = 0.012, d = 0.56). Veterans and non-Veterans did not significantly differ in performance on the delayed recall portion of the verbal learning test and did not differ on a cognitive screening test (Montreal Cognitive Assessment) or on measures of premorbid intellectual functioning (Wide Range Achievement Test-4 Reading), language (Boston Naming Test, Verbal Fluency), visual memory (Brief Visuospatial Memory Test-Revised), attention/working memory (WAIS-IV Digit Span), processing speed (WAIS-IV Digit Symbol Coding), executive function (Delis-Kaplan Executive Function System Trails and Color-Word Test), or functional capacity (UPSA-B). Because our examination of multiple outcomes might have inflated Type I error, we performed a post hoc adjustment of P values using Benjamini-Hochberg procedures and the group difference in verbal learning remained significant. CONCLUSIONS: Despite largely similar function in most domains, Veterans performed significantly more poorly in verbal list learning than their non-Veteran peers. Additional attention should be given to the understanding, assessment, and possible treatment of learning and memory differences in older Veterans, as this may be an area in which Veteran status confers additional risk or vulnerability to decline. This is the first study to compare objective neuropsychological and functional performance between older (age 65+) US Veterans and non-Veterans.

A call to action: informing research and practice in suicide prevention among individuals with psychosis.

Although it is well established that individuals living with psychosis are at increased risk for suicidal ideation, attempts, and death by suicide, several gaps in the literature need to be addressed to advance research and improve clinical practice. This Call-to-Action highlights three major gaps in our understanding of the intersection of psychosis and suicide as determined by expert consensus. The three gaps include research methods, suicide risk screening and assessment tools used with persons with psychosis, and psychosocial interventions and therapies. Specific action steps to address these gaps are outlined to inform research and practice, and thus, improve care and prognoses among persons with psychosis at risk for suicide.

A Scoping Review of Suicide Prevention Interventions for Lesbian, Gay, Bisexual, Transgender, Queer, and Other Sexual and Gender Minority Individuals.

Purpose: This scoping review summarizes the literature on suicide-specific psychological interventions among lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) people to synthesize existing findings and support future intervention research and dissemination. Methods: Electronic databases PsycInfo and PubMed were searched for reports of psychological intervention studies with suicide-related outcome data among LGBTQ+ people. A total of 1269 articles were screened, and 19 studies met inclusion criteria (k = 3 examined suicide-specific interventions tailored to LGBTQ+ people, k = 4 examined nontailored suicide-specific interventions, k = 11 examined minority stress- or LGBTQ+ interventions that were not suicide-specific, and k = 1 examined other types of interventions). Results: Synthesis of this literature was made challenging by varied study designs, and features limit confidence in the degree of internal and external validity of the interventions evaluated. The only established suicide-specific intervention examined was Dialectical Behavior Therapy, and minority stress- and LGBTQ-specific interventions rarely targeted suicidal thoughts and behaviors (STBs). Nevertheless, most interventions reviewed demonstrated support for feasibility and/or acceptability. Only five studies tested suicide-related outcome differences between an LGBTQ+ group and a cisgender/heterosexual group. These studies did not find significant differences in STBs, but certain subgroups such as bisexual individuals may exhibit specific treatment disparities. Conclusion: Given the dearth of research, more research examining interventions that may reduce STBs among LGBTQ+ people is critically needed to address this public health issue.

Person-specific dynamics between negative emotions and suicidal thoughts.

INTRODUCTION: Recent technology has enabled researchers to collect ecological momentary assessments (EMA) to examine within-person correlates of suicidal thoughts. Prior studies examined generalized temporal dynamics of emotions and suicidal thinking over brief periods, but it is not yet known how variable these processes are across people. METHOD: We use data EMA data delivered over two weeks with youth/young adults (N = 60) who reported past year self-injurious thoughts/behaviors. We used group iterative multiple model estimation (GIMME) to model group- and person-specific associations of negative emotions (i.e., fear, sadness, shame, guilt, and anger) and suicidal thoughts. RESULTS: 29 participants (48.33%) reported at least one instance of a suicidal thought and were included in GIMME models. In group level models, we consistently observed autoregressive effects for suicidal thoughts (e.g., earlier thoughts predicting later thoughts), although the magnitude and direction of this link varied from person-to-person. Among emotions, sadness was most frequently associated with contemporaneous suicidal thoughts, but this was evident for less than half of the sample, while other emotional correlates of suicidal thoughts broadly differed across people. No emotion variable was linked to future suicidal thoughts in >14% of the sample, CONCLUSIONS: Emotion-based correlates of suicidal thoughts are heterogeneous across people. Better understanding of the individual-level pathways maintaining suicidal thoughts/behaviors may lead to more effective, personalized interventions.

Associations between fearlessness about death and suicidal ideation in individuals with psychosis.

BACKGROUND: Despite high rates of suicide among people with psychosis, relatively little is known about the mechanisms underlying the transition from suicidal ideation to behavior in this population. The Interpersonal Psychological Theory of Suicide (IPTS) proposes that fearlessness about death (FAD) may play a role in this relationship. The present study tested whether constructs of the IPTS [thwarted belongingness (TB), perceived burdensomeness (PB), and FAD] were associated with the severity of suicidal ideation in a sample of adults with histories of psychosis. METHOD: 261 adults with histories of psychosis completed measures of IPTS constructs, current severity of suicidal ideation, and history of suicidal attempts. We examined differences between those with past suicide attempts and those without and conducted regression analyses to evaluate the associations among TB, PB, FAD and severity of current suicidal ideation. RESULTS: Contrary to expectations, a history of suicidal behavior was not uniquely associated with FAD. Regression analyses revealed TB × PB and FAD × PB interactions emerged as significant correlates of the severity of suicidal ideation, with the relationship between PB and suicidal ideation more pronounced at higher levels of FAD and TB. Interestingly, positive symptoms of psychosis were positively associated with PB. IMPLICATIONS: This study provides support for broadening the investigation of FAD as a contributor to suicidal ideation in individuals with psychotic symptoms. Future research investigating the role of other contributors that may influence capability for suicide (e.g., impulsivity) may add additional understanding of suicide in this population.

Restless legs symptoms increased during COVID-19 pandemic. International ICOSS-survey.

BACKGROUND AND OBJECTIVES: Restless legs syndrome (RLS) has been associated with anxiety, depression, insomnia, lifestyle factors and infections. We aimed to study the prevalence of symptoms of RLS during the COVID-19 pandemic versus pre-pandemic. We hypothesized that pre-existing RLS symptoms worsened and pandemic-related factors may have triggered new symptoms of RLS. METHODS: Adults (≥18 years) from fifteen countries across four continents participated in an online survey between May and August 2020. The harmonized questionnaire included a validated single question on RLS with response alternatives from 1 to 5 on a scale from never to every/almost every evening or night. Other measures were the Insomnia Severity Index (ISI), measures of symptoms of anxiety (GAD-2) and depression (PHQ-2), and questions on different pandemic-related factors. RESULTS: Altogether, 17 846 subjects (63.8 % women) were included in the final analyses. The mean age was 41.4 years (SD 16.1). During the pandemic, symptoms of RLS (≥3 evenings/nights per week) were more common 9.1 % (95 % CI 8.7-10.1) compared to 5.4 % (95 % CI 4.9-6.0) before the pandemic (P < 0.0001). Alltogether 1.3 % (95 % CI 1.1-1.6) respondents had new-onset symptoms (≥3 evenings/nights per week). Moderate-severe insomnia was strongly associated with RLS symptoms. The occurrences of new-onset RLS symptoms were 5.6 % (95 % CI 0.9-13.0) for participants reporting COVID-19 and 1.1 % (95 % CI 0.7-1.5) for non-COVID-19 participants. In the fully adjusted logistic regression model, the occurrence of new-onset RLS symptoms was associated with younger age, social restrictions and insomnia severity. In a similar analysis, RLS symptoms (≥3 evenings/nights per week) were associated with lower education, financial hardship, sleep apnea symptoms, use of hypnotics, insomnia severity, symptoms of depression and possible post-traumatic stress disorder. DISCUSSION: Our findings indicate that RLS symptoms were more common during the pandemic than before. Usually, the prevalence of RLS increases with age. However, during the pandemic, new-onset symptoms of RLS were more common in younger age groups. This may be due to the pandemic-related factors being more pronounced in the younger compared to the older. The association between insomnia, psychiatric symptoms and RLS warrants clinical attention.

Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.