Association Between Firearm Purchasing in Response to the COVID-19 Pandemic and Symptoms of Anxiety, Depression, and Stress, August 2021.

Introduction: Firearm sales and firearm-related injuries and deaths increased during the pandemic. Little is known about motivations for firearm purchasing in response to the COVID-19 pandemic and the mental health status of first-time purchasers. The purpose of this study was to estimate the association between firearm purchasing in response to the COVID-19 pandemic and anxiety symptoms, depressive symptoms, and stress. Methods: The authors analyzed data from a survey that approximated a nationally representative sample of American adults (N=3,528) who either did not own firearms (n=2,327) or purchased firearms for the first time in response to the pandemic (n=240). Self-reported stress, depressive symptoms, and anxiety symptoms were determined using standardized self-assessment questionnaires (Perceived Stress Scale, Patient Health Questionnaire, and Depression Anxiety Stress Scale, respectively). Using multivariable logistic regression, the association between firearm purchasing and each mental health measure were assessed after controlling for demographics and other determinants. Results: In each model, first-time firearm owners were more likely to be younger, live in urban areas, believe the government does too much for its citizens, stay home, stock up on items, and keep their children at home. First-time owners had significantly higher odds of anxiety and depressive symptoms than non-owners (AOR=1.05; 95% CI=1.04, 1.07 and AOR=1.15; 95% CI=1.04, 1.26, respectively). Conclusions: First-time firearm purchasers report higher depressive and anxiety symptoms than non-owners, suggesting that there may be a risk of suicide and other related firearm violence.

What are the odds? Poor compliance with UK loot box probability disclosure industry self-regulation.

Loot boxes are purchased in video games to obtain randomised rewards of varying value and are thus psychologically akin to gambling. Disclosing the probabilities of obtaining loot box rewards may reduce overspending, in a similar vein to related disclosure approaches in gambling. Presently, this consumer protection measure has been adopted as law only in the People's Republic of China (PRC). In other countries, the videogaming industry has generally adopted this measure as self-regulation. However, self-regulation conflicts with commercial interests and might not maximally promote public welfare. The loot box prevalence rate amongst the 100 highest-grossing UK iPhone games was 77% in mid-2021. The compliance rate with probability disclosure industry self-regulation was only 64.0%, significantly lower than that of PRC legal regulation (95.6%). In addition, UK games generally made insufficiently prominent and difficult-to-access disclosures both in-game and on the game's official website. Significantly fewer UK games disclosed probabilities on their official websites (21.3%) when compared to 72.5% of PRC games. Only one of 75 UK games (1.3%) adopted the most prominent disclosure format of automatically displaying the probabilities on the in-game purchase page. Policymakers should demand more accountable forms of industry self-regulation or impose direct legal regulation to ensure consumer protection.

Increasing resiliency and reducing mental illness stigma in post-secondary students: A meta-analytic evaluation of the inquiring mind program.

Objective: Worsening student mental health, along with more complex mental illness presentation and increased access to campus mental health services, has led to a mental health "crisis" on campuses. One way to address student mental health needs may be through mental health programs which have been found to increase resiliency and help-seeking, and reduce stigma. Participants: The effectiveness of The Inquiring Mind (TIM), a mental health promotion and mental illness stigma reduction program, was examined in 810 students from 16 Canadian post-secondary institutions. Methods and Results: Using a meta-analytic approach, TIM improved resiliency and decreased stigmatizing attitudes from pre to post, with medium effect sizes (d > .50). Analyses with those that completed the follow-up (about one-third of the sample) showed that effects were mostly retained at three months. Other outcomes also point to the program's effectiveness. Conclusion: TIM appears to be an effective program for post-secondary students. However, additional research, including randomized control trials, is needed to address study limitations.

My Deep Sea, My Backyard: a pilot study to build capacity for global deep-ocean exploration and research.

The deep ocean is the largest ecosystem on the planet, constituting greater than 90% of all habitable space. Over three-quarters of countries globally have deep ocean within their Exclusive Economic Zones. While maintaining deep-ocean function is key to ensuring planetary health, deficiencies in knowledge and governance, as well as inequitable global capacity, challenge our ability to safeguard the resilience of this vast realm, leaving the fate of the deep ocean in the hands of a few. Historically, deep-ocean scientific exploration and research have been the purview of a limited number of nations, resulting in most of humankind not knowing the deep ocean within their national jurisdiction or beyond. In this article, we highlight the inequities and need for increased deep-ocean knowledge generation, and discuss experiences in piloting an innovative project 'My Deep Sea, My Backyard' toward this goal. Recognizing that many deep-ocean endeavours take place in countries without deep-ocean access, this project aimed to reduce dependency on external expertise and promote local efforts in two small island developing states, Trinidad and Tobago and Kiribati, to explore their deep-sea backyards using comparatively low-cost technology while building lasting in-country capacity. We share lessons learned so future efforts can bring us closer to achieving this goal. This article is part of the theme issue 'Nurturing resilient marine ecosystems'.

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

Quantum Temporal Superposition: The Case of Quantum Field Theory.

Quantum field theory is completely characterized by the field correlations between spacetime points. In turn, some of these can be accessed by locally coupling to the field simple quantum systems, also known as particle detectors. In this letter we consider what happens when a quantum-controlled superposition of detectors at different space-time points is used to probe the correlations of the field. We show that, due to quantum interference effects, two detectors can gain information on field correlations that would not be accessible, otherwise. This has relevant consequences for information theoretic quantities, like entanglement and mutual information harvested from the field. In particular, the quantum control allows for extraction of entanglement in scenarios where this is, otherwise, provably impossible.

PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

The Warwick Experience of the Oncotype DX® Breast Recurrence Score® Assay as a Predictor of Chemotherapy Administration.

INTRODUCTION: Oncotype DX® analyses the expression of 21 genes within tumour tissue to determine a Recurrence Score® (RS). RS is a marker of risk for distant recurrence in oestrogen receptor-positive early breast cancer, allowing patient-specific benefit of chemotherapy to be evaluated. Our aim was to determine whether the introduction of Oncotype DX led to a net reduction in chemotherapy use. METHODS: Consecutive patients that underwent Oncotype DX at Warwick Hospital were reviewed. Patients were anonymised and re-discussed at a multidisciplinary team meeting (MDM; without RS), and treatment recommendations were recorded. This was compared to the original MDM outcome (recommendations made with RS). Differences were analysed using Wilcoxon signed-rank test. RESULTS: 67 patients were identified. Proportions of high, intermediate and low risk were 28, 33 and 39% (n = 19/22/26), respectively. Without RS, 56 (84%) patients were recommended for chemotherapy and 3 were not. The remaining 8 patients were deemed borderline for requiring chemotherapy and referred for discussion with an oncologist. With availability of RS, 34 (50%) patients were recommended for chemotherapy, and 24 (43%) patients were spared chemotherapy (p < 0.0005). The net reduction in chemotherapy was 33%. CONCLUSION: There has been a significant reduction in chemotherapy usage in patients at Warwick since the introduction of Oncotype DX.

Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer.

Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab.Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort.Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies.Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146-54. ©2017 AACR.

High-Content Biopsies Facilitate Molecular Analyses and Do Not Increase Complication Rates in Patients With Advanced Solid Tumors.

PURPOSE: Precision oncology relies on frequent pathologic, molecular, and genomic assessments of tumor tissue to guide treatment selection, evaluate pharmacodynamic effects of novel agents, and determine drug resistance mechanisms. Newer forms of analyses such as drug screens in cell lines and patient-derived xenografts demand increasing amounts of tissue material. It remains unknown how the need for serial biopsies with large numbers of tumor cores relates to tissue yields and biopsy complication rates. MATERIALS AND METHODS: In this study, we performed a retrospective analysis of 199 focal liver biopsies performed in 143 patients in the setting of oncologic research protocols (research biopsy group) over a 4-year period at a single-intervention oncology service. Practice patterns and complication rates were compared with those related to 1,522 consecutive biopsies performed in 1,154 patients in whom two cores were obtained for standard clinical management of patients (standard biopsy). RESULTS: In the research biopsy group, 1,100 tissue cores (average, 5.5 cores per procedure) were harvested and distributed to trial sponsors, internal research laboratories, and pathology services. The complication rate in this cohort was 0.5% for major complications (one of 199) and 1.0% for minor complications managed conservatively (two of 199). In the standard biopsy control group, major complications were observed in 1.4% of procedures (22 of 1,522) and minor complications in 0.2% (three of 1,522). These complication rates were not statistically different. CONCLUSION: Harvesting extra tissue cores through coaxial needles during focal liver biopsies does not increase complication rates and yields valuable tissue for additional experimental testing.

Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

Drosophila Psf2 has a role in chromosome condensation.

The condensation state of chromosomes is a critical parameter in multiple processes within the cell. Failures in the maintenance of appropriate condensation states may lead to genomic instability, mis-expression of genes, and a number of disease states. During cell proliferation, replication of DNA represents an ongoing challenge for chromosome packaging as DNA must be unpackaged for replication and then faithfully repackaged. An integral member of the DNA replication machinery is the GINS complex which has been shown to stabilize the CMG complex which is required for processivity of the Mcm2-7 helicase complex during S phase. Through examination of the phenotypes associated with a null mutation in Psf2, a member of the evolutionarily conserved GINS complex, we find that Drosophila Psf2 likely has a role in establishing chromosome condensation and that the defects associated with this mis-condensation impact M phase progression, genomic stability, and transcriptional regulation.

Multiple functions for Drosophila Mcm10 suggested through analysis of two Mcm10 mutant alleles.

DNA replication and the correct packaging of DNA into different states of chromatin are both essential processes in all eukaryotic cells. High-fidelity replication of DNA is essential for the transmission of genetic material to cells. Likewise the maintenance of the epigenetic chromatin states is essential to the faithful reproduction of the transcriptional state of the cell. It is becoming more apparent that these two processes are linked through interactions between DNA replication proteins and chromatin-associated proteins. In addition, more proteins are being discovered that have dual roles in both DNA replication and the maintenance of epigenetic states. We present an analysis of two Drosophila mutants in the conserved DNA replication protein Mcm10. A hypomorphic mutant demonstrates that Mcm10 has a role in heterochromatic silencing and chromosome condensation, while the analysis of a novel C-terminal truncation allele of Mcm10 suggests that an interaction with Mcm2 is not required for chromosome condensation and heterochromatic silencing but is important for DNA replication.

Social support buffers the impact of functional impairments on caregiver psychological well-being in the context of brain tumor and other cancers.

OBJECTIVE: This study investigated the association between functional impairments of individuals with cancer and caregiver psychological well-being, and examined the moderating effect of social support. METHODS: Sixty-three caregivers (71% female) of individuals with brain tumor (n=27) and other cancers (n=36) were recruited from community services. Caregivers rated their psychological well-being on the World Health Organisation Quality of Life measure Brief version, social support on a brief version of the Social Support Questionnaire, and the individuals' functional impairments on the Patient Competency Rating Scale. RESULTS: For caregivers of individuals with brain tumor, better psychological well-being was associated with lower functional impairment in all domains (r(s)=0.33-38, p<0.05), except for cognitive difficulties. For caregivers of individuals with other cancers, better psychological well-being was associated with lower functional impairment in all domains (r(s)=0.30-0.49, p<0.05), with the exception of activities of daily living. For the total caregiver sample, better psychological well-being was significantly correlated with overall functional impairment (r=0.34, p<0.005) and satisfaction with support (r=0.40, p<0.005). Caregivers supporting individuals with greater functional impairment had better psychological well-being if they were highly satisfied with their social support. CONCLUSIONS: Effective social support is particularly important for caregivers who support individuals with poorer functional status, and this study highlights the need to evaluate caregiver social support interventions in the context of cancer.

Gender, smoking status, and risk behavior attitudes explain adolescents' patterns of nicotine replacement therapy use.

Treatment studies provide minimal support for nicotine replacement therapy (NRT) with youth; however, survey studies suggest that adolescents use NRT, and may engage in inappropriate use. The current study sought to examine patterns of NRT use and risk factors for use to further aid smoking cessation efforts including prevention of potential misuse. In-school surveys assessing socio-demographic and behavioral factors associated with NRT use, gum or patch, were completed by 4078, predominantly African American, high school students. Approximately 5% of students reported former or current use of NRT products: 42% gum, 29% patch, and 29% both gum and patch. Among smokers, 5.4% reported use of both NRT gum and patch, with exclusive use of gum twice as likely as exclusive use of the patch. Those with high-risk-taking attitudes were more likely than low-risk takers (3% vs. 1%) to report use of both products, with exclusive gum use more prevalent than patch use. A cumulative logit model revealed males, risk takers, and/or smokers were at greatest odds for NRT use. Among this adolescent sample, NRT gum was used more often than the patch. Adolescent males, risk takers, and/or smokers appear more likely to use NRT (gum and/or patch) compared to their counterparts, despite limited empirical support for effective use of these products as cessation aids among adolescents. Smoking cessation and prevention programs may emphasize appropriate NRT use, specifically within these populations.

Medication use among inner-city patients after hospital discharge: patient-reported barriers and solutions.

OBJECTIVES: To better characterize medication-related problems among inner-city patients after hospital discharge and to suggest potential interventions. PATIENTS AND METHODS: Between August 9, 2005, and April 3, 2006, we interviewed 84 patients hospitalized with acute coronary syndromes at Grady Memorial Hospital in downtown Atlanta, GA, and contacted them by telephone about 2 weeks later. English-speaking patients who managed their own medications were studied. Patients reported their adherence with filling prescriptions and taking medications after discharge, as well as barriers to and potential enablers of proper medication use. RESULTS: Most of the 84 respondents were African American (74 [88%]), male (49 [58%]), and middle-aged (mean age, 54.5 years). Only 40% of patients filled their prescriptions on the day of discharge, 20% filled them 1 or 2 days later, and 18% waited 3 to 9 days; 22% had not filled their prescriptions by the time of the follow-up telephone call (median, 12 days; interquartile range, 8-18 days). Transportation, cost, and wait times at the pharmacy were cited as the main barriers. Many patients reported it was somewhat or very difficult to understand why they were prescribed medications (21%), how to take them (11%), or how to reconcile them with the medications they had been taking before hospitalization (16%). About half the patients (40 [48%]) reported some degree of nonadherence after discharge. Patients noted that several forms of assistance could improve medication use after discharge, including lower medication costs (75%), a follow-up telephone call (68%), transportation to the pharmacy (65%), pharmacist counseling before discharge (64%), and a pillbox (56%). CONCLUSION: Patients often delay filling prescriptions and have difficulty understanding medication regimens after hospital discharge. Interventions that reduce medication costs, facilitate transportation, improve medication counseling, and supply such organizing aids as pillboxes might be beneficial.

Development of an illustrated medication schedule as a low-literacy patient education tool.

OBJECTIVE: Patients with low health literacy have difficulty understanding prescription drug labels and other medication instructions. This article describes the development, implementation, and preliminary evaluation of an illustrated medication schedule (a "pill card") that depicts a patient's daily medication regimen using pill images and icons. METHODS: Participants in a randomized controlled trial who were assigned to receive the pill card intervention described their use of the card and its perceived effectiveness. Responses were analyzed by level of patient literacy and other characteristics. RESULTS: Among the 209 respondents, 173 (83%) reported using the pill card when they initially received it, though use declined to 60% approximately 3 months later. Patients with inadequate or marginal literacy skills, less than high school education, or cognitive impairment were most likely to refer to the card on a regular basis initially and at 3 months (p<0.05). Most pill card users (92%) rated the tool as very easy to understand, and 94% found it helpful for remembering important medication information, such as the name, purpose, or time of administration. CONCLUSION: Nearly all patients considered an illustrated medication schedule to be a useful and easily understood tool to assist with medication management. Patients with limited literacy skills, educational attainment, or cognitive function referred to the aid with greater frequency. PRACTICE IMPLICATIONS: Picture-based instructions promote better understanding of prescription medications, particularly among patients with limited literacy skills or cognitive impairment, and should be used more widely in practice.

Predictors of medication self-management skill in a low-literacy population.

BACKGROUND: Patients' ability to manage medications is critical to chronic disease control. Also known as medication management capacity (MMC), it includes the ability to correctly identify medications and describe how they should be taken. OBJECTIVE: To evaluate the effects of low literacy, medication regimen complexity, and sociodemographic characteristics on MMC. DESIGN: Cross-sectional analysis of enrollment data from participants in a randomized trial. PARTICIPANTS: Patients with coronary heart disease in an inner-city clinic. MEASUREMENTS: Medication management capacity was measured with the Drug Regimen Unassisted Grading Scale (DRUGS), which scores subjects' ability to identify, open, describe the dose, and describe the timing of their medications. DRUGS overall and component scores were compared by literacy, Mini Mental State Exam score, regimen complexity (number of prescription medications), and sociodemographic characteristics. RESULTS: Most of the 152 participants were elderly (mean age 65.4 years), women (54.6%), and African American (94.1%). Approximately half (50.7%) had inadequate literacy skills, and 28.9% had marginal skills. In univariate analysis, MMC was significantly associated with literacy (P<.001), and this effect was driven by the ability to identify medications. In multivariable models, patients with inadequate literacy skills had 10 to 18 times the odds of being unable to identify all of their medications, compared with those with adequate literacy skills (P<.05). CONCLUSIONS: Adults with inadequate literacy skills have less ability to identify their medications. Techniques are needed to better educate low-literacy patients about their medications, as a potential strategy to enhance adherence.