Hemoglobin scavenger receptor CD163 as a potential biomarker of hemolysis induced hepatobiliary injury in sickle cell disease.

Sickle cell disease (SCD) associated chronic hemolysis promotes oxidative stress, inflammation and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD related hepatobiliary injury has not been fully elucidated yet. Here, we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane bound CD163. Hemolysis and increase in hepatic heme, hemoglobin and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that HO-1 positively regulates membrane bound CD163 expression independent of NRF2 signaling in SCD liver. We further demonstrate that of the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD associated hepatobiliary injury. Understanding the role of HO-1 in membrane bound CD163 regulation may help identify novel therapeutic targets for hemolysis induced chronic liver injury.

Oral Nicotine Gum Discussions on Twitter: Content Analysis.

BACKGROUND: Oral nicotine gum such as LUCY, which comes in colorful packaging, mimicking traditional chewing gum, is becoming popular. Many brands of gum have not been approved by the FDA for smoking cessation. This study examined public discourse about, including sentiment toward, oral nicotine gum on Twitter. METHODS: We used Twitter's Streaming Application Programming Interface to collect data from January 1, 2021, to December 21, 2021, using "nicotine gum" and/or "#nicotinegum" search terms (N = 19 171 unique tweets were collected). We used an inductive approach to become familiar with the data, generated a codebook, and conducted a content analysis on (n = 2152) tweets. RESULTS: Cessation (n = 716, 33.3%), personal experience (n = 370, 17.2%), and addiction to gum (n = 135, 6.3%) were the most prevalent themes. Cessation tweets primarily discussed cigarette smoking cessation (n = 418, 58.4% of cessation tweets) and successful cessation experiences (n = 155, 21.6%). Other identified themes pertained to using nicotine gum for cognitive enhancement or catching a "buzz" (n = 102, 4.7%), marketing (n = 98, 4.6%), using nicotine gum with other substances (n = 90, 4.2%), and adverse effects (n = 63, 2.9%). Sentiment analysis results revealed that 675 (44.2%) tweets were categorized as neutral, 605 (39.6%) tweets were classified as positive, and 248 tweets (16.2%) were negative. CONCLUSIONS: About one-third of tweets in our corpus mentioned nicotine gum in the context of smoking cessation. Most nicotine gum-related posts conveyed positive and neutral sentiments. Future studies should consider adding novel nicotine gum-specific search terms as well as exploring other social media platforms to gain more insights about these products. IMPLICATIONS: Our findings suggest that Twitter has the potential to track and facilitate conversations between those seeking cigarette cessation advice and those who have successfully quit tobacco by using nicotine gum. Monitoring of promotional content from nicotine gum companies is needed to ensure these products are not appealing to youth and nonusers of tobacco.

Can ultrasound-guided medial branch blocks be used to select patients for cervical facet joint radiofrequency neurotomy? - A matched retrospective cohort validation study.

BACKGROUND: Medial branch blocks are used to select patients for cervical facet joint radiofrequency neurotomy (CRFN). Blocks are typically performed under fluoroscopic guidance (FLB). The validity of ultrasound guided blocks (USB) is not well established. No prior research has compared cervical USB versus FLB validity using CRFN outcome as the criterion standard. OBJECTIVE: To evaluate cervical USB versus FLB validity using CRFN outcome as the criterion standard. METHODS: Demographic and outcome data were extracted from the EMRs of two affiliated MSK pain management clinics for all patients between 2015 and 2023 inclusive who had cervical USB leading to CRFN. CRFN outcomes of each USB patient were compared to a matched FLB patient from the RFN outcome database of the same clinics. Matching variables included patient age, sex, pain duration, diagnostics/prognostic block paradigm and CRFN number. Each patient completed a NRS pain score and Pain Disability Quality-of-Life Questionnaire (PDQQ) just before and 3-months post-CRFN. At repeat CRFN, patients provided a retrospective estimate of the duration and average magnitude (%) of relief following the CRFN. RESULTS: USB and FLB groups were comprised of 27 patients (58 RFNs) and 38 patients (58 RFNs) respectively. Post RFN NRS pain severity and PDQQ-S scores demonstrated comparable (p > 0.05) absolute improvements, proportion of patients achieving ≥50% improvement, and attainment of MCID. Retrospective estimates of pain relief magnitude and duration were also comparable. CONCLUSIONS: This study finds cervical USB and FLB to be comparably valid as defined by their ability to predict CRFN outcome. Within the limitations of operator competence, USB can be used to select patients for CRFN.

LungCARE: Encouraging Shared Decision-Making in Lung Cancer Screening-a Randomized Trial.

BACKGROUND: Lung cancer screening (LCS) is recommended for individuals at high risk due to age and smoking history after a shared decision-making conversation. However, little is known about best strategies for incorporating shared decision-making, especially in a busy primary care setting. OBJECTIVE: To develop a novel tool, Lung Cancer Assessment of Risk and Education (LungCARE) to guide LCS decisions among eligible primary care patients. DESIGN: Pilot cluster randomized controlled trial of LungCARE versus usual care. PARTICIPANTS: Patients of providers in a university primary care clinic, who met criteria for LCS. INTERVENTION: Providers were randomized to LungCARE intervention or control. LungCARE participants completed a computer tablet-based video assessment of lung cancer educational needs in the waiting room prior to a primary care visit. Patient and provider both received a summary handout of patient concerns and responses. MAIN MEASURES: All eligible patients completed baseline interviews by telephone. One week after the index visit, participants completed a follow-up telephone survey that assessed patient-physician discussion of LCS, referral to and scheduling of LCS, as well as LCS knowledge and acceptability of LungCARE. Two months after index visit, we reviewed patients' electronic health records (EHRs) for evidence of a shared decision-making conversation and referral to and receipt of LCS. KEY RESULTS: A total of 66 participants completed baseline and follow-up visits (34: LungCARE; 32: usual care). Mean age was 65.9 (± 6.0). Based on EHR review, compared to usual care, LungCARE participants were more likely to have discussed LCS with their physicians (56% vs 25%; p = 0.04) and to be referred to LCS (44% vs 13%; p < 0.02). Intervention participants were also more likely to complete LCS (32% vs 13%; p < 0.01) and had higher knowledge scores (mean score 6.5 (± 1.7) vs 5.5 (± 1.4; p < 0.01). CONCLUSIONS: LungCARE increased discussion, referral, and completion of LCS and improved LCS knowledge. CLINICAL TRIAL REGISTRATION: NCT03862001.

Scalable surveillance of e-cigarette products on Instagram and TikTok using computer vision.

INTRODUCTION: Instagram and TikTok, video-based social media platforms popular among adolescents, contain tobacco-related content despite the platforms' policies prohibiting substance-related posts. Prior research identified themes in e-cigarette-related social media posts using qualitative or text-based machine learning methods. We developed an image-based computer vision model to identify e-cigarette products in social media images and videos. METHODS: We created a dataset of 6,999 Instagram images labeled for 8 object classes: mod or pod devices, e-juice containers, packaging boxes, nicotine warning labels, e-juice flavors, e-cigarette brand names, and smoke clouds. We trained a DyHead object detection model using a Swin-Large backbone, evaluated the model's performance on 20 Instagram and TikTok videos, and applied the model to 14,072 e-cigarette-related promotional TikTok videos (2019-2022; 10,276,485 frames). RESULTS: The model achieved the following mean average precision scores on the image test set: e-juice container: 0.89; pod device: 0.67; mod device: 0.54; packaging box: 0.84; nicotine warning label: 0.86; e-cigarette brand name: 0.71; e-juice flavor name: 0.89; and smoke cloud: 0.46. The largest number of TikTok videos - 9,091 (65%) - contained smoke clouds, followed by mod and pod devices detected in 6,667 (47%) and 5,949 (42%) videos respectively. Prevalence of nicotine warning labels was the lowest, detected in 980 videos (7%). CONCLUSIONS: Deep learning-based object detection technology enables automated analysis of visual posts on social media. Our computer vision model can detect the presence of e-cigarettes products in images and videos, providing valuable surveillance data for tobacco regulatory science. IMPLICATIONS: Prior research identified themes in e-cigarette-related social media posts using qualitative or text-based machine learning methods. We developed an image-based computer vision model to identify e-cigarette products in social media images and videos.We trained a DyHead object detection model using a Swin-Large backbone, evaluated the model's performance on 20 Instagram and TikTok videos featuring at least two e-cigarette objects, and applied the model to 14,072 e-cigarette-related promotional TikTok videos (2019-2022; 10,276,485 frames).The deep learning model can be used for automated, scalable surveillance of image- and video-based e-cigarette-related promotional content on social media, providing valuable data for tobacco regulatory science. Social media platforms could use computer vision to identify tobacco-related imagery and remove it promptly, which could reduce adolescents' exposure to tobacco content online.

Doxorubicin and zoledronate treatment in a dog with hemophagocytic histiocytic sarcoma.

A 6-year-old castrated male greyhound dog was referred for hemophagocytic histiocytic sarcoma (HHS) diagnosed following splenectomy. Severe thrombocytopenia, mild hypoalbuminemia, mild hypocholesterolemia, and mild hyperbilirubinemia were present. Abdominal ultrasound findings were concerning for hepatic metastasis. Doxorubicin and zoledronate combination therapy was initiated. The dog improved clinically and its thrombocytopenia, hypoalbuminemia, and hyperbilirubinemia resolved. The dog appeared well for 147 d before tumor progression was noted. The dog was treated with lomustine as a final measure, with no response. The dog survived for 6 mo with chemotherapy. To the authors' knowledge, this is the first report of clinical benefit of chemotherapy for HHS. Key clinical message: Doxorubicin should be considered for treating canine HHS since this variant of the disease is historically refractory to lomustine. Further research regarding efficacy of doxorubicin and zoledronate should be pursued.

Traitement à la doxorubicine et au zolédronate chez un chien atteint de sarcome histiocytaire hémophagocytaire. Un lévrier mâle castré de 6 ans a été vu pour un sarcome histiocytaire hémophagocytaire (HHS) diagnostiqué à la suite d'une splénectomie. Une thrombopénie sévère, une hypoalbuminémie légère, une hypocholestérolémie légère et une hyperbilirubinémie légère étaient présentes. Les résultats de l'échographie abdominale étaient préoccupants quant aux métastases hépatiques. Un traitement associant doxorubicine et zolédronate a été instauré. Le chien s'est amélioré cliniquement et sa thrombocytopénie, son hypoalbuminémie et son hyperbilirubinémie ont disparu. Le chien semblait en bonne santé pendant 147 jours avant de constater une progression tumorale. Le chien a été traité avec de la lomustine comme mesure finale, sans réponse. Le chien a survécu 6 mois grâce à la chimiothérapie. À la connaissance des auteurs, il s'agit du premier rapport faisant état d'un bénéfice clinique de la chimiothérapie pour le HHS.Message clinique clé :La doxorubicine doit être envisagée pour traiter le HHS canin puisque cette variante de la maladie est historiquement réfractaire à la lomustine. Des recherches plus approfondies concernant l'efficacité de la doxorubicine et du zolédronate devraient être poursuivies.(Traduit par Dr Serge Messier).

Pediatric Preanesthesia Anxiety and Factors of Family Satisfaction.

PURPOSE: Pediatric patients scheduled for procedures with anesthesia experience stress and feelings of anxiety, but frequently lack the opportunity to report their feelings. Pediatric patient anxiety may be related to internal (patient perceptions/emotions) or external (demographic/family knowledge/satisfaction) factors. The purpose of the study was to explore patient reports of anxiety in young school-age through adolescent ages, and factors of family satisfaction before a scheduled procedure with anesthesia. DESIGN: Cross-sectional, descriptive, and correlational. METHODS: A voluntary survey including family-report of patient age and past anesthesia, type of procedure, family satisfaction factors (knowledge of anesthesia; perioperative concerns), and patient-report of anxiety with a visual analog scale (0-10) was offered to eligible families at their preanesthesia clinic appointment. FINDINGS: Completed surveys from 80 families (mean age of patient = 12 years; range 7-17 years) showed legally authorized guardians (LAGs) felt the preanesthesia visit helped them understand anesthesia information, but they also had concerns, such as complications and pain. Patient anxiety ratings ranged from 0 to 10 (M = 3.3, SD = 3.1), and were slightly higher for patients 11 years and younger (M = 3.8; SD = 3.4). Anxiety ratings were not significantly correlated with other factors measured. CONCLUSIONS: Pediatric patients, ages 7-17, report preanesthesia anxiety levels ranging from "not at all" to "worst imaginable," unrelated to demographic or family factors. Family members have perioperative concerns that need to be addressed before scheduled procedures. There is an impetus for improvement in psychosocial assessment and health care team collaboration to meet needs in a family-centered preanesthesia care model.

Optimized Production of Disulfide-Bonded Fungal Effectors in Escherichia coli Using CyDisCo and FunCyDisCo Coexpression Approaches.

Effectors are a key part of the arsenal of plant-pathogenic fungi and promote pathogen virulence and disease. Effectors typically lack sequence similarity to proteins with known functional domains and motifs, limiting our ability to predict their functions and understand how they are recognized by plant hosts. As a result, cross-disciplinary approaches involving structural biology and protein biochemistry are often required to decipher and better characterize effector function. These approaches are reliant on high yields of relatively pure protein, which often requires protein production using a heterologous expression system. For some effectors, establishing an efficient production system can be difficult, particularly those that require multiple disulfide bonds to achieve their naturally folded structure. Here, we describe the use of a coexpression system within the heterologous host Escherichia coli, termed CyDisCo (cytoplasmic disulfide bond formation in E. coli) to produce disulfide bonded fungal effectors. We demonstrate that CyDisCo and a naturalized coexpression approach termed FunCyDisCo (Fungi CyDisCo) can significantly improve the production yields of numerous disulfide-bonded effectors from diverse fungal pathogens. The ability to produce large quantities of functional recombinant protein has facilitated functional studies and crystallization of several of these reported fungal effectors. We suggest this approach could be broadly useful in the investigation of the function and recognition of a broad range of disulfide bond-containing effectors.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Hyperbolic trade-off: The importance of balancing trial and subject sample sizes in neuroimaging.

Here we investigate the crucial role of trials in task-based neuroimaging from the perspectives of statistical efficiency and condition-level generalizability. Big data initiatives have gained popularity for leveraging a large sample of subjects to study a wide range of effect magnitudes in the brain. On the other hand, most task-based FMRI designs feature a relatively small number of subjects, so that resulting parameter estimates may be associated with compromised precision. Nevertheless, little attention has been given to another important dimension of experimental design, which can equally boost a study's statistical efficiency: the trial sample size. The common practice of condition-level modeling implicitly assumes no cross-trial variability. Here, we systematically explore the different factors that impact effect uncertainty, drawing on evidence from hierarchical modeling, simulations and an FMRI dataset of 42 subjects who completed a large number of trials of cognitive control task. We find that, due to an approximately symmetric hyperbola-relationship between trial and subject sample sizes in the presence of relatively large cross-trial variability, 1) trial sample size has nearly the same impact as subject sample size on statistical efficiency; 2) increasing both the number of trials and subjects improves statistical efficiency more effectively than focusing on subjects alone; 3) trial sample size can be leveraged alongside subject sample size to improve the cost-effectiveness of an experimental design; 4) for small trial sample sizes, trial-level modeling, rather than condition-level modeling through summary statistics, may be necessary to accurately assess the standard error of an effect estimate. We close by making practical suggestions for improving experimental designs across neuroimaging and behavioral studies.

Reliability of task-evoked neural activation during face-emotion paradigms: Effects of scanner and psychological processes.

Assessing and improving test-retest reliability is critical to efforts to address concerns about replicability of task-based functional magnetic resonance imaging. The current study uses two statistical approaches to examine how scanner and task-related factors influence reliability of neural response to face-emotion viewing. Forty healthy adult participants completed two face-emotion paradigms at up to three scanning sessions across two scanners of the same build over approximately 2 months. We examined reliability across the main task contrasts using Bayesian linear mixed-effects models performed voxel-wise across the brain. We also used a novel Bayesian hierarchical model across a predefined whole-brain parcellation scheme and subcortical anatomical regions. Scanner differences accounted for minimal variance in temporal signal-to-noise ratio and task contrast maps. Regions activated during task at the group level showed higher reliability relative to regions not activated significantly at the group level. Greater reliability was found for contrasts involving conditions with clearly distinct visual stimuli and associated cognitive demands (e.g., face vs. nonface discrimination) compared to conditions with more similar demands (e.g., angry vs. happy face discrimination). Voxel-wise reliability estimates tended to be higher than those based on predefined anatomical regions. This work informs attempts to improve reliability in the context of task activation patterns and specific task contrasts. Our study provides a new method to estimate reliability across a large number of regions of interest and can inform researchers' selection of task conditions and analytic contrasts.

Examination of prostate-specific antigen (PSA) screening in military and civilian men: analysis of the 2018 behavioral risk factor surveillance system.

PURPOSE: To determine whether military men report different prostate-specific antigen (PSA) screening rates than civilian men and if shared decision-making (SDM) is associated with PSA screening. METHODS: We used data from the 2018 Behavioral Risk Factor Surveillance System and included 101,901 men (26,363 military and 75,538 civilian men) in the analysis conducted in 2021. We conducted binomial logistic regression analyses to determine covariate-adjusted associations between military status and receiving a PSA test in the last 2 years. We then added patient reports of SDM to the model. Finally, we looked at the joint effects of military status and SDM on the receipt of a PSA test in the last 2 years. RESULTS: Military men had 1.1 times the odds of PSA testing compared to civilian men (95% CI 1.1, 1.2) after adjusting for SDM and sociodemographic and health covariates. When examining the joint effect of military status and SDM, military and civilian men had over three times the odds of receiving a PSA test in the last 2 years if they had reported SDM (OR 3.5 and OR 3.4, respectively) compared to civilian men who did not experience SDM. CONCLUSION: Military men are slightly more likely to report receiving a PSA test in the last 2 years compared to civilian men. Additionally, results show SDM plays a role in the receipt of a PSA test in both populations. These findings can serve as a foundation for tailored interventions to promote appropriate SDM for PSA screening in civilian, active duty, and veteran healthcare systems.

Real-time assessment of positive and negative affective fluctuations and mood lability in a transdiagnostic sample of youth.

BACKGROUND: Emotional lability, defined as rapid and/or intense affect fluctuations, is associated with pediatric psychopathology. Although numerous studies have examined labile mood in clinical groups, few studies have used real-time assessments in a well-characterized transdiagnostic sample, and no prior study has included participants with disruptive mood dysregulation disorder (DMDD). The present study leverages ecological momentary assessment (EMA) to assess emotional lability in a transdiagnostic pediatric sample. METHODS: One hundred thirty participants ages 8-18 with primary diagnoses of DMDD, attention-deficit/hyperactivity disorder (ADHD), an anxiety disorder (ANX), or healthy volunteers completed a previously validated 1-week EMA protocol. Clinicians determined diagnoses based on semi-structured interviews and assessed levels of functional impairment. Participants reported momentary affective states and mood change. Composite scores of fluctuations in positive and negative affect were generated. Affect fluctuations were compared between diagnostic groups and tested for their association with functional impairment. RESULTS: Diagnostic groups differed in levels of negative and positive emotional lability. DMDD patients demonstrated the highest level of labile mood compared with other groups. Emotional lability was associated with global impairment in the whole sample. CONCLUSIONS: Both positive and negative emotional lability is salient in pediatric psychopathology and is associated with functional impairment, particularly in DMDD youth.

Associations Between Resting Heart Rate, Resting Blood Pressure, Psychological Variables and Pain Processing in Chronic Whiplash-Associated Disorder: A Cross-Sectional Study.

OBJECTIVE: Autonomic nervous system dysfunction has been implicated in chronic whiplash-associated disorder (WAD). However, the relationship between autonomic variables (e.g., resting heart rate and blood pressure) and clinical factors in chronic WAD is not well understood. This study sought to examine the associations between resting heart rate, resting blood pressure, pain processing and psychological variables in chronic WAD and in pain-free controls. DESIGN: Secondary analysis of a cross-sectional study. SETTING: University clinical research laboratory. SUBJECTS: Thirty-six people with chronic WAD Grade II (mean [SD] age 40.1 [14.6] years, 28 females) and 25 pain-free controls (35.6 [13.0] years, 17 females). METHODS: Participants had resting heart rate, systolic and diastolic blood pressure measured. Pain processing measures comprised: (i) pain pressure threshold at the cervical spine, hand and leg, (ii) temporal summation at the cervical spine and hand, and (iii) conditioned pain modulation. Psychological outcomes included measures of kinesiophobia, pain catastrophizing and post-traumatic stress symptoms. Correlations between autonomic variables, pain processing and psychological variables were determined (P < .05, 5% FDR). RESULTS: No significant correlations between autonomic and pain processing variables, or autonomic and psychological variables were found in the chronic WAD group. In the control group, diastolic blood pressure was positively correlated with cervical spine pressure pain threshold (r = 0.53, P = .007). CONCLUSIONS: An association between blood pressure and pain sensitivity was observed in the control group but not the chronic WAD group. Such an association appears to be disrupted in chronic WAD, which may infer involvement of autonomic pathways in the pathophysiology of this condition.

Trial and error: A hierarchical modeling approach to test-retest reliability.

The concept of test-retest reliability indexes the consistency of a measurement across time. High reliability is critical for any scientific study, but specifically for the study of individual differences. Evidence of poor reliability of commonly used behavioral and functional neuroimaging tasks is mounting. Reports on low reliability of task-based fMRI have called into question the adequacy of using even the most common, well-characterized cognitive tasks with robust population-level effects, to measure individual differences. Here, we lay out a hierarchical framework that estimates reliability as a correlation divorced from trial-level variability, and show that reliability tends to be underestimated under the conventional intraclass correlation framework through summary statistics based on condition-level modeling. In addition, we examine how reliability estimation between the two statistical frameworks diverges and assess how different factors (e.g., trial and subject sample sizes, relative magnitude of cross-trial variability) impact reliability estimates. As empirical data indicate that cross-trial variability is large in most tasks, this work highlights that a large number of trials (e.g., greater than 100) may be required to achieve precise reliability estimates. We reference the tools TRR and 3dLMEr for the community to apply trial-level models to behavior and neuroimaging data and discuss how to make these new measurements most useful for future studies.

Survival outcomes for cancer types with the highest death rates for adolescents and young adults, 1975-2016.

BACKGROUND: Five-year relative survival for adolescent and young adult (AYA) patients with cancer diagnosed at the ages of 15 to 39 years is 85%. Survival rates vary considerably according to the cancer type. The purpose of this study was to analyze long-term survival trends for cancer types with the highest mortality among AYAs to determine where the greatest burden is and to identify areas for future research. METHODS: Using data from the Surveillance, Epidemiology, and End Results cancer registry and the National Center for Health Statistics, the authors examined the incidence, mortality, and survival for the 9 cancer types with the highest mortality rates in this age group from 1975 to 2016. JPSurv, new survival trend software, was used in the analysis. RESULTS: Results suggested significant improvements in 5-year relative survival for brain and other nervous system tumors, colon and rectum cancer, lung and bronchus cancer, acute myeloid leukemia, and non-Hodgkin lymphoma (all P values < .05). Limited or no improvement in survival was found for female breast cancer, cervical cancer, ovarian cancer, and bone and joint sarcomas. CONCLUSIONS: Five-year relative survival for multiple cancer types in AYAs has improved, but some common cancer types in this group still show limited survival improvements (eg, ovarian cancer). Survival improvements in colorectal cancer have been overshadowed by its rising incidence, which suggests a substantial disease burden. Future research should focus on female breast, bone, ovarian, and cervical cancers, which have seen minimal or no improvements in survival. LAY SUMMARY: Survival trends for adolescents and young adults with cancer are presented from a 40-year period. Although survival progress is noted for brain cancer, lung cancer, acute myeloid leukemia, and colon and rectum cancer, the incidence of colon and rectum cancer remains high. Minimal progress is evident for female breast, bone, ovarian, and cervical cancers, which are in need of renewed focus.

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

BACKGROUND: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. METHODS: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. FINDINGS: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks. INTERPRETATION: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. FUNDING: University of Birmingham, University of Oxford.

Maternal obesity in sheep impairs foetal hepatic mitochondrial respiratory chain capacity.

BACKGROUND: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype. MATERIAL AND METHODS: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes. RESULTS: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related protein content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO. CONCLUSIONS: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.

Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

Examination of individual and multiple comorbid conditions and health-related quality of life in older cancer survivors.

PURPOSE: Older cancer survivors (≥ 65 years at diagnosis) are at high-risk for multimorbidity (2 + comorbid conditions). However, few studies have utilized a generalizable sample of older cancer survivors to understand how individual comorbid conditions, as opposed to total comorbidity burden, are associated with health-related quality of life (HRQOL). We examined associations between HRQOL outcomes (pain, fatigue, physical function), individual comorbidities (cardiovascular disease [CVD], lung disease, diabetes, arthritis) and total comorbidity (cancer-only, cancer + 1 condition, cancer + 2 or more conditions). METHODS: Utilizing a population-based sample of 2019 older cancer survivors, we tested associations between comorbid conditions and the HRQOL outcomes using generalized linear models. HRQOL domains were assessed using Patient-Reported Outcome Measurement Information System® (PROMIS®) measures. Comorbidity was assessed via self-report. RESULTS: Cancer survivors with lung disease reported significantly worse physical functioning (ß = - 4.96, p < 0.001), survivors with arthritis reported significantly higher pain (ß = 4.37, p < 0.001), and survivors with CVD reported significantly higher fatigue (ß = 3.45, p < 0.001) compared to survivors without each condition. Having cancer + 1 condition was not as strongly associated with all outcomes as when individual conditions were tested (e.g. pain: ß = 3.09, p < 0.001). Having 2+ comorbidities had a stronger association with all outcomes (e.g. physical function: ß = - 7.51, p < 0.001) than examining conditions individually. CONCLUSIONS: Knowing the specific comorbid condition profile of an older cancer survivor provides insight into specific HRQOL outcomes that may be impaired in cancer survivorship, but understanding total comorbidity burden, regardless of the specific conditions, sheds light on survivors at-risk for multiple impairments in HRQOL. This information, taken together, can inform risk-stratified survivorship care.

Emotional distractors and attentional control in anxious youth: eye tracking and fMRI data.

Attentional control theory suggests that high cognitive demands impair the flexible deployment of attention control in anxious adults, particularly when paired with external threats. Extending this work to pediatric anxiety, we report two studies utilising eye tracking (Study 1) and functional magnetic resonance imaging (Study 2). Both studies use a visual search paradigm to examine anxiety-related differences in the impact of threat on attentional control at varying levels of task difficulty. In Study 1, youth ages 8-18 years (N = 109), completed the paradigm during eye tracking. Results indicated that youth with more severe anxiety took longer to fixate on and identify the target, specifically on difficult trials, compared to youth with less anxiety. However, no anxiety-related effects of emotional distraction (faces) emerged. In Study 2, a separate cohort of 8-18-year-olds (N = 72) completed a similar paradigm during fMRI. Behaviourally, youth with more severe anxiety were slower to respond on searches following non-threatening, compared to threatening, distractors, but this effect did not vary by task difficulty. The same interaction emerged in the neuroimaging analysis in the superior parietal lobule and precentral gyrus-more severe anxiety was associated with greater brain response following non-threatening distractors. Theoretical implications of these inconsistent findings are discussed.