'Interesting' or 'boring': Modifying the implicit association task to measure implicit fire interest in an adolescent community sample.

The efficacy of explicit measures in assessing fire interest is often compromised by social desirability biases, presenting a challenge for early intervention programs aimed at preventing firesetting behaviour. The current study aimed to validate a novel fire interest Implicit Association Task (IAT), as a more reliable measure of implicit fire interest in adolescents. An Australian community adolescent sample of 85 participants, aged 10-17 (M = 13.65, SD = 1.81), completed a series of questionnaires, and the novel fire interest IAT. Based on self-reports, participants were classified as firelighters (n = 52) or non-firelighters (n = 33). IAT outcomes revealed an inclination towards associating "fire" with "interesting." Notably, firelighters, compared to non-firelighters, performed significantly quicker during hypothesis-consistent trials of the IAT where fire-images were paired with interesting-words. Moreover, a weak correlation emerged between the speed of responses in these hypothesis-consistent IAT trials and self-reported fire interest. This investigation is one of the few that examined the efficacy of implicit measures of fire interest and is the first to do so using a modified IAT. With continued refinement, the fire interest IAT could be successfully used to assist with early intervention programs aimed at preventing child firesetting behaviour. PsychINFO Code: 3230.

Immune Checkpoint Inhibitors in Geriatric Oncology.

PURPOSE OF REVIEW: This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. RECENT FINDINGS: ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.

A lentivirus-vectored feline erythropoietin gene therapy strategy in tissue culture and rodent models for the potential treatment of chronic renal disease-associated anemia.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of a third-generation lentivirus-based vector encoding the feline erythropoietin (EPO) (feEPO) gene in vitro and in rodent models in vivo. This vector incorporates a genetic mechanism to facilitate the termination of the therapeutic effect in the event of supraphysiologic polycythemia, the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene." ANIMALS: CFRK cells and replication-defective lentiviral vectors encoding feEPO were used for in vitro experiments. Eight Fischer rats were enrolled in the pilot in vivo study, 24 EPO-deficient mice were used in the initial mouse study, and 15 EPO-deficient mice were enrolled in the final mouse study. METHODS: Efficacy of a third-generation lentivirus encoding feEPO was determined in vitro using western blot assays. Subsequently, in a series of rodent experiments, animals were administered the viral vector in progressively increasing inoculation doses with serial measurements of blood packed cell volume (PCV) over time. RESULTS: We documented production of feEPO protein in transduced CRFK cells with subsequent cessation of production when treated with the HSV-TK substrate ganciclovir. In vivo, we demonstrated variably persistent elevated PCV values in treated rats and mice with eventual return to baseline values over time. CLINICAL RELEVANCE: These results provide justification for a lentiviral gene therapy approach to the treatment of nonregenerative anemia associated with chronic renal disease in cats.

Soluble immune-checkpoint factors: a potential immunotherapy biomarker.

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.

Awareness of Hypertension, Hypercholesterolemia, and Diabetes Mellitus and Associated Characteristics in Russian Adults.

Russia has higher cardiovascular disease (CVD) mortality compared to other European countries. The major CVD risk factors are age, male sex, and three conditions, namely hypertension, hypercholesterolemia, and diabetes mellitus (DM). This study aimed to assess awareness of these three conditions among Russian adults (N = 3803) and the associated socio-demographic, lifestyle, and health characteristics. We used cross-sectional data from a randomly drawn population-based sample of Russians aged 35-69 years, who participated in the Know Your Heart (KYH) study conducted in Arkhangelsk and Novosibirsk between 2015-2018. Participants' self-reported awareness of hypertension, hypercholesterolemia, and DM was assessed against the measures at the KYH health check (blood pressure, cholesterol, HbA1c and/or use of medication for each condition). Prevalence estimates for the awareness were age- and sex-standardized to the Standard European Population. Socio-demographic, lifestyle, and health-related correlates of the awareness were investigated using logistic regression modelling. Among participants with hypertension (N = 2206), hypercholesterolemia (N = 3171), and DM (N = 329) recorded at a health check, 79%, 45%, and 61% self-reported these conditions, respectively. Higher awareness of hypercholesterolemia and hypertension was associated with older age, female sex, nonsmoking status, obesity, and history of CVD diagnoses. Low household income and history of CVD diagnoses were associated with being aware of DM. The awareness rates of hypertension were relatively high, whereas awareness rates of hypercholesterolemia and DM were relatively low. CVD prevention and early intervention could be improved in Russia through increasing the awareness of the risk factors.

A Harmonised Approach to Curating Research-Ready Datasets for Asthma, Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD) in England, Wales and Scotland Using Clinical Practice Research Datalink (CPRD), Secure Anonymised Information Linkage (SAIL) Databank and DataLoch.

Background: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations. Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons. Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.

Correction: Cook et al. An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats. Viruses 2022, 14, 2429.

In the original publication [...].

Impact of DREAMS interventions on attitudes towards gender norms among adolescent girls and young women: Findings from a prospective cohort in Kenya.

The DREAMS partnership aims to deliver a comprehensive package to reduce HIV incidence among adolescent girls and young women (AGYW), including through shifting gender norms. We evaluate DREAMS' effect on attitudes towards gender norms in two Kenyan settings. AGYW aged 15-22 in Nairobi (n = 852) and Gem (n = 761) were randomly selected for cohort enrolment in 2017-18 and followed-up to 2019. We described the proportion of AGYW and their male peers with equitable attitudes towards gender norms, using an adapted version of the GEM scale. We estimated the association between self-reported invitation to DREAMS (in 2017-18) and AGYW's attitudes towards two dimensions of gender norms, and then applied a causal inference framework to estimate the difference in the proportion of AGYW with equitable attitudes under the counterfactual scenarios that all versus none were DREAMS beneficiaries. We estimated that overall, 90.2% versus 87.1% of AGYW would have equitable norms around sexual and reproductive health decision-making in Nairobi if all versus none were DREAMS beneficiaries (+3.1; 95%CI:-2.5, +9.0). In Gem, we estimated a risk difference of +1.0 (89.6% vs 88.6%, 95%CI: -3.6,+5.6). There was no evidence for an effect of DREAMS on attitudes towards violence-related norms (Nairobi: 82.7% vs 82.2%, +0.5; 95%CI: -5.3,+6.5; Gem: 44.3% vs 48.2%, -3.9; 95%CI: -11.7,+3.0). We found no evidence of an impact of DREAMS invitation on individual attitudes towards gender norms. In some cases, equitable attitudes at enrolment left limited scope for improvement, and additional effort may be required to shift inequitable violence attitudes among both AGYW and their male peers.

Adeno-Associated Virus Type 9-Mediated Gene Therapy of Choline Acetyltransferase-Deficient Mice.

The enzyme choline acetyltransferase (ChAT) synthesizes acetylcholine from acetyl-CoA and choline at the neuromuscular junction and at the nerve terminals of cholinergic neurons. Mutations in the ChAT gene (CHAT) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for Chat (Chat-/-) die at birth. To circumvent the lethality of this model, we crossed mutant mice possessing loxP sites flanking Chat exons 4 and 5 with mice that expressed Cre-ERT2. Injection of tamoxifen (Tx) at postnatal (P) day 11 in these mice induced downregulation of Chat, autonomic failure, weakness, and death. However, a proportion of Chatflox/flox-Cre-ERT2 mice receiving at birth an intracerebroventricular injection of 2 × 1013 vg/kg adeno-associated virus type 9 (AAV9) carrying human CHAT (AAV9-CHAT) survived a subsequent Tx injection and lived to adulthood without showing signs of weakness. Likewise, injection of AA9-CHAT by intracisternal injection at P28 after the onset of weakness also resulted in survival to adulthood. The expression of Chat in spinal motor neurons of Chatflox/flox-Cre-ERT2 mice injected with Tx was markedly reduced, but AAV-injected mice showed a robust recovery of ChAT expression, which was mainly translated by the human CHAT RNA. The biodistribution of the viral genome was widespread but maximal in the spinal cord and brain of AAV-injected mice. No significant histopathological changes were observed in the brain, liver, and heart of AAV-injected mice after 1 year follow-up. Thus, AAV9-mediated gene therapy may provide an effective and safe treatment for patients severely affected with CHAT-CMS.

Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors.

Importance: Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined. Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs. Design, Setting, and Participants: This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line. Exposure: Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs). Main Outcomes and Measures: The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS. Results: Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001). Conclusions and Relevance: In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

The relationship between physical performance and alcohol consumption levels in Russian adults.

Investigating the relationship between alcohol consumption and physical performance, we used data from the 2015-2018 Know Your Heart study on 4215 adults aged 35-69 from Arkhangelsk and Novosibirsk, Russia. We classified participants' drinking status into non-drinking, non-problem drinking, hazardous drinking, and harmful drinking based on their self-reported drinking behaviors. To evaluate physical performance, we developed a Composite Physical Performance Scale (CPPS), which combined the results of three functional tests: grip strength (GS), closed-eyes balance, and chair rises (CR). We applied multivariable linear regression to assess the relationship between alcohol consumption and CPPS score, and ordinal logistic regression to explore the associations between alcohol consumption and the three functional tests separately. The results showed that harmful drinking was associated with lower CPPS scores compared to non-problem drinking. Among harmful drinking men, the decrease in CPPS scores was explained by all three tests equally and exceptionally by GS among women. Non-drinking was also associated with decreased CPPS, linked to lower GS and CR scores in men, and only lower GS scores in women. The study revealed a reduced physical performance in the non-drinking and harmful drinking groups compared to non-problem drinking.

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

Patient-reported symptoms and interest in symptom monitoring in HCC treated with locoregional therapies: A qualitative study.

BACKGROUND: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system. METHODS: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes. RESULTS: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring. CONCLUSIONS: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC.

Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.

Association of C-reactive protein with future development of diabetes: a population-based 7-year cohort study among Norwegian adults aged 30 and older in the Tromsø Study 2007-2016.

OBJECTIVES: The extent to which observed associations between high-sensitivity C-reactive protein (hs-CRP) and incident diabetes are explained by obesity and hypertension remains unclear. This study aimed to investigate the association of hs-CRP with developing diabetes in a Norwegian general population sample. DESIGN: A cohort study using two population-based surveys of the Tromsø Study: the sixth survey Tromsø6 (2007-2008) as baseline and the seventh survey Tromsø7 (2015-2016) at follow-up. SETTING: Tromsø municipality of Norway, a country with increasing proportion of older adults and a high prevalence of overweight, obesity and hypertension. PARTICIPANTS: 8067 women and men without diabetes, aged 30-87 years, at baseline Tromsø6 who subsequently also participated in Tromsø7. OUTCOME MEASURES: Diabetes defined by self-reported diabetes, diabetes medication use and/or HbA1c≥6.5% (≥48 mmol/mol) was modelled by logistic regression for the association with baseline hs-CRP, either stratified into three quantiles or as continuous variable, adjusted for demographic factors, behavioural and cardiovascular risk factors, lipid-lowering medication use, and hypertension. Interactions by sex, body mass index (BMI), hypertension or abdominal obesity were assessed by adding interaction terms in the fully adjusted model. RESULTS: There were 320 (4.0%) diabetes cases after 7 years. After multivariable adjustment including obesity and hypertension, individuals in the highest hs-CRP tertile 3 had 73% higher odds of developing diabetes (OR 1.73; p=0.004; 95% CI 1.20 to 2.49) when compared with the lowest tertile or 28% higher odds of incidence per one-log of hs-CRP increment (OR 1.28; p=0.003; 95% CI 1.09 to 1.50). There was no evidence for interaction between hs-CRP and sex, hypertension, BMI or abdominal obesity. CONCLUSIONS: Raised hs-CRP was associated with future diabetes development in a Norwegian adult population sample. The CRP-diabetes association could not be fully explained by obesity or hypertension.

The RIC Recruitment & Retention Materials Toolkit - a resource for developing community-informed study materials.

Clinical trials face many challenges with meeting projected enrollment and retention goals. A study's recruitment materials and messaging convey necessary key information and therefore serve as a critical first impression with potential participants. Yet study teams often lack the resources and skills needed to develop engaging, culturally tailored, and professional-looking recruitment materials. To address this gap, the Recruitment Innovation Center recently developed a Recruitment & Retention Materials Content and Design Toolkit, which offers research teams guidance, actionable tips, resources, and customizable templates for creating trial-specific study materials. This paper seeks to describe the creation and contents of this new toolkit.

The Late Asymptomatic and Terminal Immunodeficiency Phases in Experimentally FIV-Infected Cats-A Long-Term Study.

Feline immunodeficiency virus (FIV) is a lentivirus in the family Retroviridae that infects domestic cats resulting in an immunodeficiency disease featuring a progressive and profound decline in multiple sets of peripheral lymphocytes. Despite compelling evidence of FIV-associated immunopathology, there are conflicting data concerning the clinical effects of FIV infection on host morbidity and mortality. To explore FIV-associated immunopathogenesis and clinical disease, we experimentally inoculated a cohort of four specific pathogen-free kittens with a biological isolate of FIV clade C and continuously monitored these animals along with two uninfected control animals for more than thirteen years from the time of inoculation to the humane euthanasia endpoint. Here, we report the results obtained during the late asymptomatic and terminal phases of FIV infection in this group of experimentally FIV-infected cats.

Poor Air Quality Is Linked to Stress in Honeybees and Can Be Compounded by the Presence of Disease.

Climate change-related extreme weather events have manifested in the western United States as warmer and drier conditions with an increased risk of wildfires. Honeybees, essential for crop pollination in California, are at the center of these extreme weather events. We associated the maximum daily temperature and air quality index values with the performance of colonies placed in wildfire-prone areas and determined the impact of these abiotic stressors on gene expression and histopathology. Our results indicate that poor air quality was associated with higher maximum daily temperatures and a lower gene expression level of Prophenoloxidase (ProPO), which is tied to immune system strength; however, a higher gene expression level of Vitellogenin (Vg) is tied to oxidative stress. There was a positive relationship between Varroa mites and N. ceranae pathogen loads, and a negative correlation between Varroa mites and Heat Shock Protein 70 (HSP70) gene expression, suggesting the limited ability of mite-infested colonies to buffer against extreme temperatures. Histological analyses did not reveal overt signs of interaction between pathology and abiotic stressors, but N. ceranae infections were evident. Our study provides insights into interactions between abiotic stressors, their relation to common biotic stressors, and the expression of genes related to immunity and oxidative stress in bees.