Low Baseline Levels Research Articles

Symptoms of anxiety but not depression before start of taxane-based chemotherapy are associated with peripheral neuropathy: a multicenter study in women with breast cancer

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, especially after taxane-based therapy. This study aimed to examine the relationship between symptoms of anxiety and depression before the start of taxane-based chemotherapy and the development of CIPN in women with breast cancer.MethodsIn this prospective study, women with breast cancer receiving taxane-based (neo)adjuvant chemotherapy were recruited from four hospitals in the Netherlands. Patients completed questionnaires assessing anxiety and depressive symptoms before treatment and CIPN before treatment (T0), 6 weeks after start of treatment (T1), after the last cycle of chemotherapy (T2), and 6 months after the end of treatment (T3). Mixed model analyses were used to investigate whether medium/high levels of anxiety or depression at baseline are associated with the level of CIPN during and after treatment.ResultsAmong the 61 participating women, 14 (23%) reported medium/high levels of anxiety and 29 (47.5%) reported medium/high levels of depressive symptoms at baseline. The group of women with medium/high baseline levels of anxiety showed a significantly higher increase in CIPN during and after chemotherapy than women with low baseline levels of anxiety (p < .001). No relationship between depressive symptoms at baseline and the development of CIPN was found.ConclusionThis study showed that baseline medium to high levels of anxiety but not depressive symptoms impacted the development of CIPN during and in the 6 months after treatment.

MP34-11 EFFECT OF ANASTROZOLE ON SPERM CONCENTRATION IN MALE PATIENTS WITH IDIOPATHIC INFERTILITY

You have accessJournal of UrologyCME1 May 2022MP34-11 EFFECT OF ANASTROZOLE ON SPERM CONCENTRATION IN MALE PATIENTS WITH IDIOPATHIC INFERTILITY Bryan Naelitz, Carlos Munoz-Lopez, Neel Parekh, Scott Lundy, and Sarah Vij Bryan NaelitzBryan Naelitz More articles by this author , Carlos Munoz-LopezCarlos Munoz-Lopez More articles by this author , Neel ParekhNeel Parekh More articles by this author , Scott LundyScott Lundy More articles by this author , and Sarah VijSarah Vij More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002588.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Anastrozole, a selective aromatase inhibitor, may be prescribed as empiric medical therapy in men with idiopathic infertility. The goal of this study is to identify patient factors associated with an improvement in semen parameters in patients treated with anastrozole. METHODS: We performed a single-center, retrospective cohort study of men prescribed anastrozole for idiopathic infertility. History and physical examination data were captured from the medical record, along with hormone and semen parameters. Exclusion criteria included history of prior exogenous testosterone use, grade II or III varicocele, recent scrotal surgery, and pre-treatment normozoospermia. The primary outcome was an upgrade in World Health Organization semen concentration category (WHO-SCC). Univariate logistic regression was used to identify predictors of WHO-SCC upgrade, while linear regression was used to model the association between predictor variables and change in semen concentration. RESULTS: 40 men were included for analysis. The median age was 35 (IQR: 31-38) and median BMI was elevated at 42 m/kg2 (IQR: 33-53). 40% (16/40) of men exhibited an upgrade in WHO-SCC after starting anastrozole and were labeled as responders. Non-responders included the 43% (17/40) of patients with no WHO-SCC change and the 18% (7/40) of men who experienced a downgrade (Figure). Median sperm concentration increased from 2.4 to 3.9 M/mL following initiation of therapy (p=0.002). Across the cohort, levels of testosterone (409 vs 210 ng/dL, p <0.0001), LH (8.1 vs 6.2 IU/L, p=0.0003), and FSH (9.3 vs. 5.3 IU/mL, p <0.0001) increased following treatment with anastrozole. Logistic regression showed that patients with greater baseline semen concentration were more likely to experience a WHO-SCC upgrade following initiation of anastrozole (OR: 1.25, 95% CI: 1.04-1.55, p=0.03). Linear regression revealed that lower baseline levels of FSH were generally associated with improvement in semen concentration (β: −0.28 M/IU, 95% CI: −0.65 to 0.03 M/IU, p=0.08). CONCLUSIONS: A subset of men with idiopathic infertility experience clinical improvement in semen parameters after initiating anastrozole therapy. Men with higher pre-treatment sperm concentrations and lower baseline FSH levels may be more likely to respond to treatment. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e582 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bryan Naelitz More articles by this author Carlos Munoz-Lopez More articles by this author Neel Parekh More articles by this author Scott Lundy More articles by this author Sarah Vij More articles by this author Expand All Advertisement PDF DownloadLoading ...

Islamic praying changes stress-related hormones and genes.

Islamic praying (Namaz) can be considered a mental, spiritual, and physical practice. The study aimed to investigate the early effect of Namaz on stress-related hormones and the expression of stress-induced genes such as IL6 and BDNF. Eighty-three healthy women and men who continually practice Namaz participated in the study. The saliva samples were taken before and after Namaz to measure cortisol and alpha-amylase hormone levels. Also, to evaluate the expression of BDNF and IL6 genes, 11 specimens were selected randomly. Based on baseline sampling, the participants were classified into three groups: cortisol levels lower than 5, between 5–15, and upper than 15 ng/ml. The results indicated that cortisol significantly increased and decreased in the first and third groups after Namaz, respectively. In addition, the increase of alpha-amylase also occurred in subjects with a low baseline level of its concentration. Regarding genetic expression examination, there was a significant decrease in BDNF gene expression after the Namaz. In addition, the change of cortisol and alpha-amylase hormones after Namaz related to the baseline level changed to approach the optimal range after Namaz. These findings were reported for the first time and need more studies.

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy.

Simple SummaryPatients treated with antibiotics have worse outcomes from cancer immunotherapy. While antibiotics are known to affect intestinal flora, it is not clear how they affect overall immune function. The aim of our study was to identify differences in immune parameters according to antibiotic exposure. Among 251 total patients, the 135 (54%) who received antibiotics had lower response rates and shorter survival. We identified significant differences in multiple antibodies according to antibiotic exposure, including antibodies specific for nucleolin, MDA5, c-reactive protein, LC1, heparin sulfate, Matrigel, and CENP.B. In lung cancer patients, antibiotics were associated with differences in IFN-γ, IL-8, and macrophage inflammatory protein cytokines. Administration of antibiotics to patients receiving cancer immunotherapy is associated with changes in circulating antibodies and cytokines, although it is not clear if antibiotics cause these differences. Given the frequency of antibiotic use in cancer populations and potentially detrimental effects on immunotherapy outcomes, more research in this area may guide patient management.Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.

Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Longitudinal associations between social media use, mental well-being and structural brain development across adolescence

Youth of today grow up in a digital social world but the effects on well-being and brain development remain debated. This study tracked longitudinal associations between structural brain development, social media use and mental well-being.The study demonstrated two pathways of heterogeneity in brain development. First, adolescents who used social media more than their peers showed higher baseline cortical thickness in lateral prefrontal cortex (PFC) and medial PFC; and stronger decreases in the lateral PFC and temporal parietal junction. In contrast, adolescents with lower mental well-being showed lower baseline levels of surface area in the medial PFC and posterior superior temporal sulcus relative to their peers. Whereas the associations between structural brain development and well-being remained significant after correction for multiple testing, the results for social media use did not survive FDR correction.These findings demonstrate that although social media use and mental well-being were both associated with differential trajectories of brain development, the associations we report are distinct. These results show a nuanced perspective on the presumed relations between social media use and well-being and provide a starting point to further examine neural mechanisms that could explain which adolescents thrive by social media and which might be harmed.

Circulating acyl and des-acyl ghrelin levels in obese adults: a systematic review and meta-analysis

Ghrelin is the only known orexigenic gut hormone, and its synthesis, secretion and degradation are affected by different metabolic statuses. This meta-analysis aimed to investigate the potential differences in plasma acyl ghrelin (AG) and des-acyl ghrelin (DAG) concentrations between normal weight and obese adults. Systematic literature searches of PubMed, Embase and Web of Science through October 2021 were conducted for articles reporting AG or DAG levels in obesity and normal weight, and 34 studies with 1863 participants who met the eligibility criteria were identified. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to evaluate group differences in circulating AG and DAG levels. Pooled effect size showed significantly lower levels of baseline AG (SMD: − 0.85; 95% CI: − 1.13 to − 0.57; PSMD < 0.001) and DAG (SMD: − 1.06; 95% CI: − 1.43 to − 0.69; PSMD < 0.001) in obese groups compared with healthy controls, and similar results were observed when subgroup analyses were stratified by the assay technique or storage procedure. Postprandial AG levels in obese subjects were significantly lower than those in controls when stratified by different time points (SMD 30 min: − 0.85, 95% CI: − 1.18 to − 0.53, PSMD < 0.001; SMD 60 min: − 1.00, 95% CI: − 1.37 to − 0.63, PSMD < 0.001; SMD 120 min: − 1.21, 95% CI: − 1.59 to − 0.83, PSMD < 0.001). In healthy subjects, a postprandial decline in AG was observed at 120 min (SMD: − 0.42; 95% CI: − 0.77 to − 0.06; PSMD = 0.021) but not in obese subjects (SMD: − 0.28; 95% CI: − 0.60 to 0.03; PSMD = 0.074). The mean change in AG concentration was similar in both the obese and lean health groups at each time point (ΔSMD30min: 0.31, 95% CI: − 0.35 to 0.97, PSMD = 0.359; ΔSMD60min: 0.17, 95% CI: − 0.12 to 0.46, PSMD = 0.246; ΔSMD120min: 0.21, 95% CI: − 0.13 to 0.54, PSMD = 0.224). This meta-analysis strengthens the clinical evidence supporting the following: lower baseline levels of circulating AG and DAG in obese individuals; declines in postprandial circulating AG levels, both for the healthy and obese individuals; a shorter duration of AG suppression in obese subjects after meal intake. These conclusions have significance for follow-up studies to elucidate the role of various ghrelin forms in energy homeostasis.

Metabolomic profiling in small vessel disease identifies multiple associations with disease severity.

Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity.We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54 764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia.Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence.Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in small vessel disease. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.

Implementing an electronic health record dashboard for safe anticoagulant management: learning from qualitative interviews with existing and potential users to develop an implementation process

BackgroundFacilitating appropriate care delivery using electronic health record (digital health) tools is increasing. However, frequently used determinants frameworks seldom address key barriers for technology-associated implementation.MethodsSemi-structured interviews were conducted in two contexts: the national Veterans Health Affairs (VA) following implementation of an electronic dashboard, a population health tool, and the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) prior to implementation of a similar electronic dashboard. The dashboard is designed for pharmacist or nurse use to monitor safe outpatient anticoagulant prescribing by physicians and other clinicians We performed rapid qualitative inquiry analysis and selected implementation strategies. Through a stakeholder focus group session, we selected implementation strategies to address determinants and facilitate implementation in the MAQI2 sites.ResultsAmong 45 interviewees (32 in VA, 13 in MAQI2), we identified five key determinants of implementation success: (1) clinician authority and autonomy, (2) clinician self-identity and job satisfaction, (3) documentation and administrative needs, (4) staffing and work schedule, and (5) integration with existing information systems. Key differences between the two contexts included concerns about information technology support and prioritization within MAQI2 (prior to implementation) but not VA (after implementation) and concerns about authority and autonomy that differed between the VA (higher baseline levels, more concerns) and MAQI2 (lower baseline levels, less concern).ConclusionsThe successful implementation of electronic health record tools requires unique considerations that differ from other types of implementation, must account for the status of implementation, and should address the effects of the tool deployment on clinical staff authority and autonomy. Interviewing both post-implementation and pre-implementation users can provide a robust understanding of implementation determinants.

Toripalimab Plus Paclitaxel and Carboplatin as Neoadjuvant Therapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma.

IntroductionImmune checkpoint inhibitors (ICIs) are effective in the treatment of advanced esophageal squamous cell carcinoma (ESCC); however, their efficacy in locally advanced resectable ESCC and the potential predictive biomarkers have limited data.MethodsIn this study, locally advanced resectable ESCC patients were enrolled and received neoadjuvant toripalimab (240 mg, day 1) plus paclitaxel (135 mg/m2, day 1) and carboplatin (area under the curve 5 mg/mL per min, day 1) in each 3-week cycle for 2 cycles, followed by esophagectomy planned 4-6 weeks after preoperative therapy. The primary endpoints were safety, feasibility, and the major pathological response (MPR) rate; the secondary endpoints were the pathological complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS). Association between molecular signatures/tumor immune microenvironment and treatment response was also explored.ResultsTwenty resectable ESCC patients were enrolled. Treatment-related adverse events (AEs) occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related AEs. Sixteen patients underwent surgery without treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Among the 16 patients, the MPR rate was 43.8% (7/16) and the pCR rate was 18.8% (3/16). The abundance of CD8+ T cells in surgical specimens increased (P = .0093), accompanied by a decreased proportion of M2-type tumor-associated macrophages (P = .036) in responders upon neoadjuvant therapy. Responders were associated with higher baseline gene expression levels of CXCL5 (P = .03) and lower baseline levels of CCL19 (P = .017) and UMODL1 (P = .03).ConclusionsThe combination of toripalimab plus paclitaxel and carboplatin is safe, feasible, and effective in locally advanced resectable ESCC, indicating its potential as a neoadjuvant treatment for ESCC.Clinical Trial registrationNCT04177797

Workplace vaccination opportunity against COVID-19 contributed to high perceived organizational support of employees in Japan: A prospective cohort study.

ObjectivesPerceived organizational support is a broad perception by employees about the extent to which their employer values their contributions and cares about their well‐being. We examined the relationship between workplace vaccination opportunities for COVID‐19 provided by companies and increases and decreases in perceived organizational support, using a prospective cohort study.MethodsThis study was conducted between December 2020 and December 2021 using a self‐administered questionnaire survey in Japan. In total, 18 560 people responded to the follow‐up, and were included in this study. The odds ratios (ORs) for the association between company‐arranged vaccination opportunities and high perceived organizational support at the follow‐up for participants (a) with low perceived organizational support at the baseline (n = 4971), and (b) with high perceived organizational support at the baseline (n = 6912) were separately estimated using a multilevel logistic model.ResultsThe OR of high perceived organizational support at the follow‐up after low baseline levels was significantly higher in participants given a vaccination opportunity than those not given this opportunity (OR 1.49; 95% confidence interval [CI] 1.32–1.67; p < .001). The OR of high perceived organizational support at the follow‐up after high baseline levels was also significantly highly in participants given a vaccination opportunity than not (OR 1.38; 95% CI 1.23–1.54; p < .001). These significant differences remained after adjusting for workplace infection control measures.ConclusionsEmployee health support provided through a workplace vaccination program can contribute to high perceived organizational support.

Reducing levels of C-Reactive Protein: An eight-week, open-label clinical trial of three oral supplements

C-reactive protein (CRP) is a protein in the blood that increases with inflammation, and high CRP levels measured with high-sensitivity CRP (hs-CRP) tests can indicate higher risk of heart attack or stroke. Several over-the-counter oral supplements reduce CRP levels. This eight-week, open-label clinical trial investigated whether Vitamin C, ginger, or curcumin were most effective at reducing hs-CRP levels in healthy individuals with low baseline hs-CRP levels. Thirty healthy male and female participants were enrolled in one of three trial treatment arms: Vitamin C (1000 mg/day), ginger (2000 mg/day), and curcumin (1000 mg/day). hs-CRP levels were collected at baseline and after eight weeks of oral supplements. Paired t-tests were used to analyze data by age, body mass index (BMI), and baseline hs-CRP level. The primary outcome measure was mean difference between time points and 95% confidence intervals. Twenty-six people completed the study. Baseline hs-CRP levels were very low for all three intervention groups. Based on estimated mean difference, all three supplements reduced hs-CRP levels, but change at eight weeks was not statistically significant. Within the groups, ginger most consistently reduced hs-CRP levels even though the ginger group had the lowest mean baseline hs-CRP levels. Curcumin was least likely to reduce hs-CRP levels. Overall, all three interventions reduced hs-CRP levels in this group of healthy participants with low baseline levels, suggesting that these agents, which are available over-the-counter, may provide an alternative for reducing inflammation. Larger clinical trials to assess the utility of these agents are warranted.

The longitudinal association of symptom-related and psychological factors with health-related quality of life in patients with chronic pelvic pain syndrome

ObjectiveTo analyze the course of symptom-related measures, psychological variables and health-related quality of life (HRQoL) over a 12-month period, and to longitudinally examine symptom-related and psychological factors as predictors for HRQoL in male and female patients with chronic pelvic pain syndrome (CPPS). MethodsData from 125 patients aged 19–83 years at baseline attending an interdisciplinary outpatient clinic for CPPS were analyzed. Participants completed a self-administered questionnaire on subjective health issues, and a postal follow-up survey was conducted 12 months later. We assessed physical and mental HRQoL, CPPS symptom severity, pain intensity, severity of somatic, depressive and anxiety symptoms, pain catastrophizing, and data on treatments during the follow-up period. Data were analyzed using multilevel linear modelling. ResultsCPPS symptom severity, pain intensity, and pain catastrophizing significantly decreased over time. HRQoL and levels of somatic symptoms, depressive symptoms and anxiety remained stable. Lower baseline levels of somatic symptoms were associated with an increase in physical HRQoL, and lower baseline levels of depressive symptoms, anxiety and pain catastrophizing were associated with an increase in mental HRQoL after 12 months. Treatment utilization was neither related to decrease in CPPS symptom severity, pain intensity and pain catastrophizing, nor to HRQoL after 12 months. ConclusionsOur data suggest that CPPS is related to persistently diminished HRQoL. Somatic symptoms and psychological factors are important determinants of HRQoL and potential therapeutic targets. To evaluate the efficacy and impact of treatment on CPPS-related outcomes, future large-scaled studies should systematically assess detailed data about therapies patients receive in routine care.

Testing the Efficacy of ‘Unlearning’, a Mindfulness and Compassion-Based Programme for Cultivating Nonviolence in Teenagers: A Randomised Controlled Trial

Background: Most programmes developed to reduce aggressive attitudes among teenagers are based on cultivating nonviolence, a construct that has been related to compassion and, more indirectly, mindfulness. This study aims at testing the efficacy of ‘Unlearning’, a mindfulness and compassion-based programme, for reducing aggressive attitudes in adolescents.Method: A sample of 164 students from three high schools in Zaragoza (Spain) participated in the study. They were randomly assigned to (1) ‘Unlearning’, or (2) relaxation programme. Three assessment points were established: baseline, post-treatment and a 4-month follow-up. The outcome variables were the subscales of the ‘Attitudes Toward Social Aggression Scale’. Mindfulness and compassion were assessed as secondary outcomes.Results: ‘Unlearning’ did not produce changes in the primary outcomes, but significant effects were observed post-treatment in self-compassion; and in the follow-up, in self-compassion and mindfulness. The control group did not experience any change post-treatment, but a significant effect in mindfulness was observed in the follow-up. The intergroup analyses indicated that ‘Unlearning’ improved self-compassion, both post-treatment (t = −2.48, p = 0.014) and after 4-months (t = −2.03, p = 0.044), although these results were not statistically significant after correcting for multiple comparisons.Conclusion: ‘Unlearning’ did not produce significant reductions in aggressive attitudes compared to the control group. The low baseline levels may have hindered the efficacy of the interventions. ‘Unlearning’ showed potential to improve self-compassion, which is related to nonviolence, and this may have positive implications for the adolescents. Future interventions should include teachers and families to enhance the effectiveness of the programmes.

Risk factors for suicide attempts among U.S. military veterans: A 7-year population-based, longitudinal cohort study.

Population-based data on risk factors for suicide attempts among veterans remains limited. A national probability sample of 2307 veterans was followed over the course of four timepoints spanning seven years to examine how a range of baseline risk factors predict incident suicide attempt. Suicide attempt data were aggregated into a single follow-up timepoint. Sixty-two veterans (3.1%) reported attempting suicide during the 7-year period. The strongest risk factors for suicide attempts were higher baseline levels of loneliness, lower baseline levels of adaptive psychosocial traits (e.g., dispositional gratitude), baseline thoughts of self-harm, and greater post-baseline trauma exposures (12.3%-41.3% of explained variance). Veterans with multiple co-occurring risk factors were at greatest risk for attempts; of veterans with 0, 1, 2, 3, and all 4 of these factors, the predicted probability of suicide attempt was 2.0%, 5.3%, 13.5%, 30.4%, and 55.0%, respectively. Baseline loneliness, dispositional gratitude, thoughts of self-harm, and new-onset traumas emerged as the strongest risk factors for suicide attempts among veterans, underscoring the potential importance of targeting these factors in prevention efforts. Veterans with multiple co-occurring risk factors have substantially greater risk for suicide attempts, suggesting that examination of multiple coinciding vulnerability factors may help improve suicide risk prediction models.

Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

Multiply marginalized: Linking minority stress due to sexual orientation, gender, and weight to dysregulated eating among sexual minority women of higher body weight.

This study assessed whether baseline levels of distal and proximal minority stressors related to sexual orientation, gender, and weight were associated with prospective risk for dysregulated eating in daily life among sexual minority women with overweight/obesity. Fifty-five sexual minority women ages 18-60 (M = 25 ± 9) with BMI > 25kg/m2 (M = 32 ± 5) completed baseline assessments of distal and proximal minority stressors due to sexual orientation, gender, and weight. Participants then completed an Ecological Momentary Assessment (EMA) protocol. For five days, participants responded to five random prompts assessing engagement in dysregulated eating (i.e., overeating, binge eating). The cumulative number of EMA-measured overeating and binge eating episodes was summed per participant. Several minority stressors related to sexual orientation, gender, and weight were associated with prospective risk for dysregulated eating behaviors during EMA. Women with higher (vs. lower) baseline levels of internalized homophobia reported more cumulative episodes of binge eating during the EMA period. Women reporting greater (vs. less) baseline sexual orientation concealment reported more episodes of overeating during the EMA period. Women with greater (vs. less) baseline weight bias experiences and internalization reported more overeating and binge eating episodes during the EMA period. Findings from this pilot study identify internalized homophobia, sexual orientation concealment, and experienced and internalized weight bias as potential risk factors for dysregulated eating behaviors among sexual minority women of higher body weight.

Role of mitochondrial DNA copy number in incident cardiovascular diseases and the association between cardiovascular disease and type 2 diabetes: A follow-up study on middle-aged women

Background and aimsMitochondrial DNA copy number (mtDNA-CN) is a surrogate biomarker of mitochondrial dysfunction and is associated with type 2 diabetes (T2D) and cardiovascular disease (CVD). However, despite being associated with both CVD and T2D, it is not known what role mtDNA-CN has in the association between T2D and CVD. Our aims were to investigate whether, (1) baseline mtDNA-CN is associated with CVD incidence and (2) mtDNA-CN has a role as a mediator between T2D and CVD. MethodWe quantified absolute mtDNA-CN by droplet digital PCR method in a population-based follow-up study of middle aged (52–65 years) women (n = 3062). The median follow-up period was 17 years. ResultsOur results show that low baseline levels of mtDNA-CN (<111 copies/μL) were associated with an increased risk of CVD (HR = 1.32, 95% CI = 1.08; 1.63) as well as with specific CVDs: coronary heart disease (HR = 1.28, 95% CI = 0.99; 1.66), stroke (HR = 1.26, 95% CI = 0.87; 1.84) and abdominal aortic aneurysm (HR = 2.61, 95% CI = 1.03; 6.62). The associations decreased but persisted even after adjustment for potential confounders. Furthermore, our results show that the total effect of T2D on future risk of CVD was reduced after controlling for mtDNA-CN and the proportion mediated by mtDNA-CN was estimated to be 4.9%. ConclusionsLower baseline mtDNA-CN is associated with incident CVD and may have a mediating effect on the association between T2D and CVD; however, this novel observation needs to be confirmed in future studies.

Abstract P239: Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors

Abstract Introduction: Copanlisib (C) is a pan-class I PI3K inhibitor, with predominant activity against the PI3K-α and -δ isoforms, approved for patients (pts) with relapsed follicular lymphoma. The PD-1 inhibitor nivolumab (N) is approved for several advanced or metastatic solid tumors. Following preclinical demonstration of the immunomodulatory activity of C (Glaeske et al. AACR 2018), we report Phase Ib results evaluating the safety and efficacy of C+N in pts with advanced solid tumors (NCT03735628). Methods: PD-1 inhibitor-naive adult pts with advanced solid tumors received C 45 mg or 60 mg i.v. (days 1, 8, and 15; 28-day cycle) and N 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles). The primary objective was determination of the recommended Phase II dose (RP2D) of C in combination with N. Secondary endpoints were safety/tolerability, pharmacokinetics (PK), and efficacy. Exploratory real-time evaluation of 77 pharmacodynamic and predictive immune cell biomarkers by flow cytometry on whole blood was performed. Results: 16 pts were treated (C 45 mg + N 240 mg, n=5; C 60 mg + N 240 mg, n=11). Median age was 65 years (range 37–89), 12 pts (75%) were male, and 8 pts (50%) had stage IV disease at diagnosis; the most common tumor types were head and neck squamous cell carcinoma (HNSCC; 7 pts) and bladder cancer (BC; 4 pts). No dose-limiting toxicities were reported. The RP2D of C+N 240 mg was 60 mg. As of 13 May 2020, 4 pts remain on treatment. The most common treatment-emergent adverse events (TEAEs) of any grade were hypertension and diarrhea (7 pts [44%] each, ≤ grade [G] 3) and maculo-papular rash and fatigue (6 pts [38%] each, ≤G3). C-related TEAEs were reported in 88% of pts, all ≤G3. AEs leading to C dose interruption/reduction were reported in 31%/19% of pts; TEAEs led to C discontinuation in 1 pt (60 mg; hematuria). Serious AEs occurred in 5 pts (31%). One G5 TEAE occurred (45 mg; general physical health deterioration, unrelated to C or N). No PK interactions were observed between C and N. Two pts had a partial response: 1 in the C 45 mg group (HNSCC) and 1 in the 60 mg group (BC; benefit sustained after 19 cycles). Stable disease was seen in 10 pts and disease progression in 3 pts; disease control rate (DCR) was 75%. Maximum decrease in circulating monocytic myeloid-derived suppressor cells (M-MDSCs; p&amp;lt;0.05) from baseline occurred on day 2 after C, returning to baseline on day 8. A significant increase in activated (HLA-DR+ and CD38+) natural killer and CD8+ T cells was seen 2 weeks post-treatment with C+N. Lower baseline levels of CD8+ Teffector memory (TEM) subset CD45RA-/CCR7- (CD3+/CD8+) seemed to associate with higher DCR. Conclusions: C+N showed acceptable safety and preliminary efficacy in pts with advanced solid tumors. The immunomodulatory effect of C on M-MDSCs was seen 2 days post-treatment, and lower TEM subset levels seemed to associate with better disease control. These results support further investigation of C+N in pts with advanced solid tumors. Funding: Bayer AG. Writing support: Complete HealthVizion. Citation Format: Benedito A. Carneiro, Robert Jotte, Nashat Gabrail, Omid Hamid, Funan Huang, Shalini Chaturvedi, Matthias Herpers, Lidia Mongay Soler, Barrett H. Childs, Aaron Hansen. Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P239.

Exploring the course of adolescent anxiety and depression: associations with white matter tract microstructure.

Cross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies investigating the course of WM microstructure are lacking. This study explored WM alterations and its relation to clinical symptoms over time in adolescents with internalizing disorders. DTI scans were acquired at baseline and after three months in 22 adolescents with clinical depression and comorbid anxiety (INT), and 21 healthy peers (HC) (age: 12-18). Tract-based spatial statistics was used for three voxelwise analyses: i) changes in WM microstructure between and within the INT and HC group; ii) associations between changes in symptom severity and changes in WM microstructure within youths with INT; and iii) associations between baseline WM parameters with changes in symptom severity within youths with INT. Data did not reveal changes in WM microstructure between or within groups over three months' time nor associations between changes in WM microstructure and changes in self-reported symptoms (analyses corrected for age, gender and puberty stage). Lower baseline levels of fractional anisotropy (FA) in the right posterior corona radiata (PCR) and right cingulum were associated with a higher decrease of depressive symptoms within the INT group. Post hoc analysis of additional WM parameters in the significant FA clusters showed that higher levels of baseline mean diffusivity and radial diffusivity in the PCR were associated with a lower decrease in depressive symptoms. Baseline WM microstructure characteristics were associated with a higher decrease in depressive symptoms over time. These findings increase our understanding of neurobiological mechanisms underlying the course of internalizing disorders in adolescents.