Does losing reduce the tendency to engage with rivals to reach mates? An experimental test.

Male-male contests for access to females or breeding resources are critical in determining male reproductive success. Larger males and those with more effective weaponry are more likely to win fights. However, even after controlling for such predictors of fighting ability, studies have reported a winner-loser effect: previous winners are more likely to win subsequent contests, while losers often suffer repeated defeats. While the effect of winning-losing is well-documented for the outcome of future fights, its effect on other behaviors (e.g. mating) remains poorly investigated. Here, we test whether a winning versus losing experience influenced subsequent behaviors of male mosquitofish (Gambusia holbrooki) toward rivals and potential mates. We housed focal males with either a smaller or larger opponent for 24 h to manipulate their fighting experience to become winners or losers, respectively. The focal males then underwent tests that required them to enter and swim through a narrow corridor to reach females, bypassing a cylinder that contained either a larger rival male (competitive scenario), a juvenile or was empty (non-competitive scenarios). The tests were repeated after 1 wk. Winners were more likely to leave the start area and to reach the females, but only when a larger rival was presented, indicating higher levels of risk-taking behavior in aggressive interactions. This winner-loser effect persisted for at least 1 wk. We suggest that male mosquitofish adjust their assessment of their own and/or their rival's fighting ability following contests in ways whose detection by researchers depends on the social context.

Protein Adsorption on Solid Surfaces: Data Mining, Database, Molecular Surface-Derived Properties, and Semiempirical Relationships.

Protein adsorption on solid surfaces is a process relevant to biological, medical, industrial, and environmental applications. Despite this wide interest and advancement in measurement techniques, the complexity of protein adsorption has frustrated its accurate prediction. To address this challenge, here, data regarding protein adsorption reported in the last four decades was collected, checked for completeness and correctness, organized, and archived in an upgraded, freely accessible Biomolecular Adsorption Database, which is equivalent to a large-scale, ad hoc, crowd-sourced multifactorial experiment. The shape and physicochemical properties of the proteins present in the database were quantified on their molecular surfaces using an in-house program (ProMS) operating as an add-on to the PyMol software. Machine learning-based analysis indicated that protein adsorption on hydrophobic and hydrophilic surfaces is modulated by different sets of operational, structural, and molecular surface-based physicochemical parameters. Separately, the adsorption data regarding four "benchmark" proteins, i.e., lysozyme, albumin, IgG, and fibrinogen, was processed by piecewise linear regression with the protein monolayer acting as breakpoint, using the linearization of the Langmuir isotherm formalism, resulting in semiempirical relationships predicting protein adsorption. These relationships, derived separately for hydrophilic and hydrophobic surfaces, described well the protein concentration on the surface as a function of the protein concentration in solution, adsorbing surface contact angle, ionic strength, pH, and temperature of the carrying fluid, and the difference between pH and the isoelectric point of the protein. When applying the semiempirical relationships derived for benchmark proteins to two other "test" proteins with known PDB structure, i.e., ß-lactoglobulin and α-lactalbumin, the errors of this extrapolation were found to be in a linear relationship with the dissimilarity between the benchmark and the test proteins. The work presented here can be used for the estimation of operational parameters modulating protein adsorption for various applications such as diagnostic devices, pharmaceuticals, biomaterials, or the food industry.

Risk Factors Associated with Survival Following Ganciclovir Prophylaxis through Day +100 in Cytomegalovirus At-Risk Pediatric Allogeneic Stem Cell Transplantation Recipients: Development of Cytomegalovirus Viremia Associated with Significantly Decreased 1-Year Survival.

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and nonrelapse mortality (NRM) in pediatric allogeneic stem cell transplantation (alloSCT) recipients. Approximately 80% of CMV seropositive alloHCT recipients will experience CMV reactivation without prophylaxis. The impacts of ganciclovir prophylaxis and subsequent CMV viremia on 1-year survival and 1-year NRM are unknown. The primary objective of this study was to determine the effect of CMV viremia on the probability of 1-year survival and 1-year NRM in pediatric alloSCT recipients receiving 100 days of ganciclovir prophylaxis. The secondary objective was to determine the effect of other risk factors on 1-year survival and 1-year NRM. All patients age 0 to 26 years who underwent alloSCT between June 2011 and May 2020 and received ganciclovir prophylaxis for 100 days at Westchester Medical Center, an academic medical center, were analyzed. Ganciclovir was administered to at-risk alloSCT recipients (donor and or recipient CMV+ serostatus) as 5 mg/kg every 12 hours from the first day of conditioning through day -1 (recipient CMV+ only) followed by 6 mg/kg every 24 hours on Monday through Friday beginning on the day of an absolute neutrophil count >750/mm3 and continuing through day +100. National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria were used to grade toxicity. NRM was analyzed using competing survival analysis with relapse death as a competing event. The log-rank and Gray tests were performed to compare the 1-year survival probabilities and NRM cumulative incidence between patients who experienced CMV viremia post-alloSCT and those who did not. Univariate Cox regression analysis was performed for the following risk factors: CMV viremia, donor source, sex, malignant disease, disease risk index, conditioning intensity, receipt of rabbit antithymocyte globulin (rATG)/alemtuzumab, graft-versus-host disease (GVHD) prophylaxis, CMV donor/recipient serostatus, grade II-IV acute GVHD, and grade 3/4 neutropenia necessitating discontinuation of ganciclovir, treating the last 3 factors as time-dependent covariates. Those with P values < .2 were included in the multivariate Cox regression analysis. Eighty-four alloSCT recipients (41 males, 43 females; median age, 10.8 years [range, .4 to 24.4 years]) were analyzed. Multivariate analysis showed significantly lower 1-year survival and significantly higher 1-year NRM in patients who developed CMV viremia compared to those who did not (P = .0036). No other risk factors were significantly associated with 1-year survival or 1-year NRM. One-year survival was significantly decreased and 1-year NRM was significantly increased in pediatric alloSCT recipients who developed CMV viremia following ganciclovir prophylaxis. No other risk factors were found to be associated with 1-year survival or 1-year NRM. Alternative CMV prophylaxis regimens that reduce CMV viremia should be investigated in pediatric alloSCT recipients at risk for CMV infection.

A randomized controlled trial of graded exposure treatment (GET living) for adolescents with chronic pain.

ABSTRACT: Graded exposure treatment (GET) is a theory-driven pain treatment that aims to improve functioning by exposing patients to activities previously feared and avoided. Combining key elements of GET with acceptance-based exposure, GET Living (GL) was developed for adolescents with chronic pain (GL). Based on robust treatment effects observed in our single-case experimental design pilot trial of GL (NCT01974791), we conducted a 2-arm randomized clinical trial comparing GL with multidisciplinary pain management (MPM) comprised of cognitive behavioral therapy and physical therapy for pain management (NCT03699007). A cohort of 68 youth with chronic musculoskeletal pain (M age 14.2 years; 81% female) were randomized to GL or MPM. Owing to COVID-19 restrictions, 54% of participants received zoom video delivered care. Assessments were collected at baseline, discharge, as well as at 3-month and 6-month follow-up. Primary outcomes were self-reported pain-related fear and avoidance. Secondary outcomes were child functional disability and parent protective responses to child pain. As hypothesized, GL improved in primary and secondary outcomes at 3-month follow-up. Contrary to our superiority hypothesis, there was no significant difference between GL and MPM. Patients reported both GL and MPM (in person and video) as credible and were highly satisfied with the treatment experience. Next steps will involve examining the single-case experimental design data embedded in this trial to facilitate an understanding of individual differences in treatment responses (eg, when effects occurred, what processes changed during treatment within the treatment arm). The current findings support GET Living and MPM for youth with chronic pain.

Topical Review: Acute and Chronic Pain Experiences in Transgender and Gender-Diverse Youth.

OBJECTIVE: To provide an overview of the existing literature on gender diversity in pediatric acute and chronic pain, propose an ecological systems model of understanding pain in transgender and gender-diverse (TGD) youth, and identify a direction for future work that will address the key knowledge gaps identified. METHODS: Relevant literature on pain and gender diversity was reviewed, drawing from adult literature where there was insufficient evidence in pediatric populations. Existing relevant models for understanding minority stress, gender and pain, and pain experiences within marginalized groups were considered with the reviewed literature to develop a pain model in TGD youth. RESULTS: While there is an abundance of literature pointing to increased risk for pain experiences amongst TGD youth, there is comparably little empirical evidence of the rates of pain amongst TGD youth, prevalence of TGD identities in pain care settings, effective pain treatments for TGD youth and unique considerations for their care, and the role intersectional factors in understanding TGD youth identities and pain. CONCLUSION: Pediatric psychologists are well-positioned to advance the research on acute and chronic pain in TGD youth, make evidence-based adaptations to clinical care for TGD youth with pain, including pain related to gender affirmation, and support colleagues within the medical system to provide more inclusive care.

Innovative treatment formats, technologies, and clinician trainings that improve access to behavioral pain treatment for youth and adults.

Chronic pain is prevalent across the life span and associated with significant individual and societal costs. Behavioral interventions are recommended as the gold-standard, evidence-based interventions for chronic pain, but barriers, such as lack of pain-trained clinicians, poor insurance coverage, and high treatment burden, limit patients' ability to access evidenced-based pain education and treatment resources. Recent advances in technology offer new opportunities to leverage innovative digital formats to overcome these barriers and dramatically increase access to high-quality, evidenced-based pain treatments for youth and adults. This scoping review highlights new advances. First, we describe system-level barriers to the broad dissemination of behavioral pain treatment. Next, we review several promising new pediatric and adult pain education and treatment technology innovations to improve access and scalability of evidence-based behavioral pain treatments. Current challenges and future research and clinical recommendations are offered.

Enhancing Exposure Treatment for Youths With Chronic Pain: Co-design and Qualitative Approach.

BACKGROUND: Increasing the access to and improving the impact of pain treatments is of utmost importance, especially among youths with chronic pain. The engagement of patients as research partners (in contrast to research participants) provides valuable expertise to collaboratively improve treatment delivery. OBJECTIVE: This study looked at a multidisciplinary exposure treatment for youths with chronic pain through the lens of patients and caregivers with the aim to explore and validate treatment change processes, prioritize and develop ideas for improvement, and identify particularly helpful treatment elements. METHODS: Qualitative exit interviews were conducted with patients and caregivers at their discharge from 2 clinical trials (ClinicalTrials.gov NCT01974791 and NCT03699007). Six independent co-design meetings were held with patients and caregivers as research partners to establish a consensus within and between groups. The results were validated in a wrap-up meeting. RESULTS: Patients and caregivers described that exposure treatment helped them better process pain-related emotions, feel empowered, and improve their relationship with each other. The research partners developed and agreed upon 12 ideas for improvement. Major recommendations include that pain exposure treatment should be disseminated more not only among patients and caregivers but also among primary care providers and the general public to facilitate an early referral for treatment. Exposure treatment should allow flexibility in terms of duration, frequency, and delivery mode. The research partners prioritized 13 helpful treatment elements. Most of the research partners agreed that future exposure treatments should continue to empower patients to choose meaningful exposure activities, break long-term goals into smaller steps, and discuss realistic expectations at discharge. CONCLUSIONS: The results of this study have the potential to contribute to the refinement of pain treatments more broadly. At their core, they suggest that pain treatments should be disseminated more, flexible, and transparent.

The Effect of Brief or Prolonged Bouts of Winning or Losing Male-Male Contests on Plasticity in Sexually Selected Traits.

AbstractFight outcomes often affect male fitness by determining their access to mates. Thus, "winner-loser" effects, where winners often win their next contest while losers tend to lose, can influence how males allocate resources toward pre- and postcopulatory traits. We experimentally manipulated the winning/losing experiences of pairs of size-matched male Gambusia holbrooki for 1 day, 1 week, or 3 weeks to test whether prior winning/losing experiences differentially affect the plasticity of male investment into either mating effort (precopulatory) or ejaculates (postcopulatory). When winner/loser pairs directly competed for a female, winners had better precopulatory outcomes than losers for three of the four traits we measured: mating attempts, successful attempts, and time spent with the female (but not aggression). However, winners and losers did not differ in either total sperm counts or sperm velocity. Interestingly, absolute male size, an important predictor of fighting success, mediated winner-loser effects on how long males then spent near a female. Compared with losers, smaller winners spent more time with the female than did larger winners, suggesting that how males respond to prior social experiences is size dependent. We discuss the general importance of controlling for inherent male condition when comparing male investment into condition-dependent traits.

Manufacture and Characterization of Good Manufacturing Practice-Compliant SARS-COV-2 Cytotoxic T Lymphocytes.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2-vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS). METHODS: Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of interferonγ (IFN-γ)+ CD4 and CD8 T cells using flow cytometry. Clinical-grade SARS-CoV-2-vCTLs were manufactured using the CliniMACS CCS. The enriched SARS-CoV-2-vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis. RESULTS: Of the convalescent donor blood samples, 93% passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that were 79% (standard error of the mean 21%) IFN-γ+ T cells. SARS-CoV-2-vCTLs displayed a highly diverse T-cell receptor repertoire with enhancement of both memory CD8 and CD4 T cells, especially in CD8 TEM, CD4 TCM, and CD4 TEMRA cell subsets. SARS-CoV-2-vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways. CONCLUSIONS: Highly functional SARS-CoV-2-vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors. CLINICAL TRIALS REGISTRATION: NCT04896606.

Evaluating the mechanisms of social cognition intervention in schizophrenia: A proof-of-concept trial.

BACKGROUND: Social cognition interventions have shown promise for improving social functioning in people with schizophrenia. However, it is unclear how changes in social cognition affect social functioning. This study evaluates the impact of a social cognition intervention (GRASP - GRoup trAining for Social skills in Psychosis) on social cognition and social functioning outcomes and explores how two mechanisms, affect and physiological arousal, may drive changes. METHOD: A two-arm single blind (assessor) randomized pilot trial comparing GRASP plus treatment-as-usual (TAU) with TAU alone in people with a diagnosis of schizophrenia. Participants were assessed with measures of social cognition, social functioning, and symptoms. All participants undertook a week-long mobile health assessment (experience sampling method) measuring social behavior and affect and used a wearable device recording autonomic activity. Assessments were performed at baseline and at week 10. RESULTS: Forty-eight participants were randomly allocated to the treatment or control condition. Individuals randomized to GRASP did not show improvements on experience sampled social behavior and social cognition measures compared to controls. However, participants in the GRASP group enjoyed social contact more and had lower levels of negative affect and higher levels of positive affect compared to controls. There was no evidence of autonomic changes (i.e., electrodermal activity) associated with social behavior resulting from the therapy. CONCLUSION: Social cognition interventions may be helpful in improving the quality of social contacts in people with schizophrenia by decreasing negative affect. Increase in social behavior may require longer periods to be evident. Future studies should consider how social cognition interventions may alter qualitative aspects associated with social behavior.

Targeting Pain Science Education in Youth With Chronic Pain: What Are the Sticking Points for Youth and Their Parents?

OBJECTIVES: An important part of providing pain science education is to first assess baseline knowledge and beliefs about pain, thereby identifying misconceptions and establishing individually-tailored learning objectives. The Concept of Pain Inventory (COPI) was developed to support this need. This study aimed to characterize the concept of pain in care-seeking youth and their parents, to examine its clinical and demographic correlates, and to identify conceptual gaps. MATERIALS AND METHODS: Following an initial interdisciplinary evaluation, a cohort of 127 youth aged 8 to 18 years, and their parents, completed a series of questionnaires. RESULTS: Parents had slightly higher COPI scores than youth did, reflecting parents' greater alignment with contemporary pain science. The moderate positive association with older age among youth ( r =.32) suggests that COPI is sensitive to cognitive development and life experiences. Youth and parent COPI responses were weakly associated ( r =0.24), highlighting the importance of targeting the concept of pain in both groups. For both parents and youth, 'Learning about pain can help you feel less pain' was the least endorsed concept. This conceptual 'gap' is a key point of intervention that could potentially lead to greater engagement with multidisciplinary pain treatment. DISCUSSION: The COPI appears useful for identifying conceptual gaps or 'sticking points'; this may be an important step to pre-emptively address misconceptions about pain through pain science education. Future research should determine the utility of COPI in assessing and treating youth seeking care for pain. The COPI may be a useful tool for tailoring pain science education to youth and their parents.

Agile development of a digital exposure treatment for youth with chronic musculoskeletal pain: protocol of a user-centred design approach and examination of feasibility and preliminary efficacy.

INTRODUCTION: Chronic pain affects a significant number of children and impacts multiple domains including social, emotional and behavioural functioning, and negatively impacts family functioning. Roughly 5% of youth with chronic pain experience moderate to severe pain-related disability, with pain-related fear and avoidance of activities being identified as substantial barriers to treatment engagement. Evidence supports targeted psychological and physical interventions to address these barriers (eg, graded-exposure treatment), but accessibility to intervention is undermined by a shortage of services outside of urban areas, high treatment-related costs, and long provider waitlists; highlighting the need to develop digitally delivered behavioural intervention, using agile and iterative study designs that support rapid development and timely dissemination. METHODS AND ANALYSIS: This study seeks to develop an effective and scalable intervention for youth with chronic pain and their caregivers. This paper presents a user-centred protocol for the development and refinement of a digital exposure treatment for youth and caregivers, as well as the study design to examine feasibility and preliminary efficacy of the treatment using single-case experimental design (SCED). Assessments include daily diaries, completed from baseline and daily throughout the intervention (~6 weeks), and at 3-month follow-up, as well as self-report measures completed at baseline, end of intervention and 3-month follow-up. Primary outcomes include treatment satisfaction, treatment expectancy, adherence to daily dairies and functional disability. Secondary outcomes are pain-related fear and avoidance of activities, pain catastrophising and pain acceptance. We will present descriptive and model-based inference analyses, based on SCED reporting guidelines. We will calculate effect sizes for each individual on each outcome. We will examine mean treatment expectancy, credibility and satisfaction scores, and patient drop-out percentage. ETHICS AND DISSEMINATION: This study is approved by the Institutional Review Board at Stanford University (protocol #53323). Findings will be actively disseminated through peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER: NCT05079984.

Navigating return to sex: A qualitative Reddit analysis of parents' perceptions about the timing of resuming sex after a birth.

OBJECTIVE: Given the many transitions that occur in the postpartum period as men and women navigate the return to sex after a birth, this study aimed to explore parents' experiences of resuming sexual activity. METHODS: This was a qualitative study that used posts from both men and women from the online public forum Reddit. Data were analysed using constructivist grounded theory. RESULTS: This study found that the discourse surrounding sexual activity in the postpartum period was dominated by an understanding that medical guidelines prohibited sex prior to six weeks after giving birth. Although some parents disagreed, many Reddit users perceived a high degree of risk in resuming sex prior to six weeks and medical expertise was highly valued as parents negotiated the return to sex. While Reddit users were largely in agreement that penetrative vaginal sex prior to six weeks was a risky activity, there was less consensus as to the risk involved in other sexual activities. CONCLUSION: This study recommends that medical practitioners initiate conversations with men and women about returning to sexual activity after a birth, and that these conversations should consider parents' emotional well-being as they resume sex. Further research is needed to establish evidence-based and comprehensive guidelines to facilitate these conversations.

Cognitive trajectories following onset of psychosis: a meta-analysis.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia, associated with poor functional outcomes. The course of cognitive function in the years following illness onset has remained a subject of debate, with a previous analysis finding no worsening, providing support for the neurodevelopmental model of schizophrenia. Since then, many more studies have reported on longitudinal cognitive performance in early psychosis, with some indicating deterioration, which does not align with this view. AIMS: This study aims to quantitatively review the literature on the longitudinal trajectory of cognitive deficits in the years following psychosis onset, in comparison with healthy controls. It is the first to also synthesise longitudinal data on social cognition. METHOD: Electronic databases ('PubMed', 'PsycInfo' and 'Scopus') were searched (to end September 2021). Meta-analyses of 25 longitudinal studies of cognition in early psychosis were conducted (1480 patients, 789 health controls). Unlike previous analyses, randomised controlled trials and those with multiple cognitive testing periods within the first year were excluded to minimise bias (PROSPERO, ID: CRD42021241525). RESULTS: Small improvements were observed for global cognition (g = 0.25, 95% CI 0.17-0.33) and individual cognitive domains, but these were comparable with healthy controls and likely an artefact of practice effects. CONCLUSIONS: There is no evidence of continued cognitive decline or improvement in the early years following psychosis onset, with a need for more studies over longer follow-up periods. Practice effects highlight the importance of including control samples in longitudinal and intervention studies. Further data are needed to evaluate the course of social cognition subdomains.

Rapid Transition to Virtual Assessment and Treatment in an Interdisciplinary Randomized Clinical Trial for Youth With Chronic Pain: Adaptations and Implications for Future Trials.

OBJECTIVES: COVID-19 abruptly halted in-person clinical care and research requiring a shift to virtual assessment and treatment. This unexpected transition of a 2-arm randomized controlled trial (RCT) examining interdisciplinary graded exposure treatment (GET Living) compared with multidisciplinary pain management for youth with chronic pain provided an opportunity to implement the first remotely delivered exposure treatment and remotely delivered biomechanical assessment for pediatric chronic pain. Here we describe these new approaches and provide lessons learned to inform future efforts in digital health care. METHODS: A total of 68 youth (M=14.2 y; 80.9% female) were enrolled in the RCT (n=31 in-person, n=5 hybrid, n=32 virtual, n=9 withdrew). Of those withdrawn, n=3 withdrew due to COVID-19 related reasons. Some RCT elements required slight modification (eg, e-consent, actigraphy deployment, recruitment, and screening), while others were significantly altered (eg, session format and lab-based biomechanical assessment). Data from exit interviews were also examined to assess perspectives on the virtual format transition. RESULTS: Results showed an increased enrollment rate when virtual care was an option (70.7%) compared with in-person (44.3%). Equivalent rates of completion for daily assessment (in-person, 72.8%; virtual, 73.3) were also observed, and participants described enhanced experience when able to complete exercises and exposures in their home environment during session (vs. a rehabilitation gym) allowing for genuine in vivo exposures (eg, household chores, riding bicycles). DISCUSSION: Overall, our data demonstrate acceptability, feasibility, and equivalent patient engagement to virtual treatment. Novel methods implemented in this RCT can inform trial design and measures of clinical endpoints for future digital health interventions.

How do psychologically based interventions for chronic musculoskeletal pain work? A systematic review and meta-analysis of specific moderators and mediators of treatment.

Psychologically based interventions aim to improve pain-related functioning by targeting pain-related fears, cognitions and behaviors. Mediation and moderation analyses permit further examination of the effect of treatment on an outcome. This systematic review and meta-analysis aims to synthetize the evidence of specific mediators and moderators (i.e., treatment targets) of psychologically based treatment effects on pain and disability. A total of 28 mediation and 11 moderation analyses were included. Thirteen mediation studies were included in a meta-analysis, and the rest was narratively synthetized. Reductions in pain-related fear (indirect effect [IE]: -0.07; 95% confidence interval [CI]: -0.11, -0.04) and catastrophizing (IE: -0.07; 95%CI: -0.14, -0.00), as well as increases in self-efficacy (IE: -0.07; 95%CI: -0.11, -0.04), mediated effects of cognitive behavioral therapy on disability but not on pain intensity, when compared to control treatments. Enhancing pain acceptance (IE: -0.17; 95%CI: -0.31, -0.03) and psychological flexibility (IE: -0.30; 95%CI: -0.41, -0.18) mediated acceptance and commitment therapy effects on disability. The narrative synthesis showed conflicting evidence, which did not support a robust moderated effect for any of the examined constructs. Overall, the methodological quality regarding mediation was low, and some key pitfalls are highlighted alongside recommendations to provide a platform for future research.

Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin's lymphoma: a phase II, non-randomized controlled trial.

BACKGROUND: Cure rates for Hodgkin's lymphoma are excellent, but excess short-term and long-term morbidities from treatment remain a concern. Immunotherapy targeting both tumor antigens and the immunosuppressive tumor microenvironment in children, adolescents, and young adults with Hodgkin's lymphoma may improve early response rates and eliminate toxic chemotherapy and radiation, thus minimizing toxicity. We conducted a phase II study to evaluate the safety and overall response rate of brentuximab vedotin and rituximab in combination with risk-adapted chemotherapy in children, adolescents, and young adults with newly diagnosed classic Hodgkin's lymphoma (cHL). METHODS: This is a prospective, phase II, non-randomized, risk-assigned study. Patients were treated and evaluated between 2012 and 2020. Eligible patients were aged ≥1 and ≤30 years old with advanced stage, intermediate-risk, and high-risk newly diagnosed cHL. Patients received four or six cycles of brentuximab vedotin (1.2 mg/kg), doxorubicin (25 mg/m2), vinblastine (6 mg/m2), dacarbazine (375 mg/m2), and rituximab (375 mg/m2). Early response was evaluated following two cycles of therapy. Involved field radiotherapy (IFRT) was restricted to high-risk patients with both bulky disease and slow response or those not in complete response at the end of chemoimmunotherapy. RESULTS: Thirty patients were enrolled, with a median age of 15 years (4-23). There were 18 intermediate-risk and 12 high-risk patients. Toxicities included grade III mucositis (3%), infusion reaction (3%), and peripheral neuropathy (6%). There was a 100% complete response rate on completion of chemoimmunotherapy. Eighteen patients (60%) achieved a rapid early response. Four patients (13%) required IFRT. The 5-year event-free and overall survival rates were 100%, with a median follow-up of 62 months (18-105). CONCLUSIONS: Immunotherapy with brentuximab vedotin, rituximab, and risk-adapted chemotherapy is safe in children, adolescents, and young adults with newly diagnosed cHL. We have demonstrated 100% complete response and 100% event-free and overall survival rates at a median 5-year follow-up, with a significant reduction in use of more toxic chemotherapy and IFRT. A larger cohort is required to confirm these preliminary findings. TRIAL REGISTRATION NUMBER: NCT02398240.

Measuring Clinically Meaningful Change in Outcomes for Youth With Chronic Pain Following Graded Exposure Treatment.

INTRODUCTION: Functional improvement is a critical outcome for individuals living with chronic pain. Graded exposure treatment (GET) has been associated with statistically significant improvements in functional outcomes for youth with chronic pain by targeting pain-related fear and avoidance. OBJECTIVE: The aim of the present study was to explore clinically meaningful change in outcomes in adolescents with chronic pain following participation in a GET, and to then classify patients as treatment responders versus nonresponders. MATERIALS AND METHODS: Participants included 27 youth (Mage=13.5) with chronic pain enrolled in a recently published single-arm randomized baseline trial of GET Living. Reliable change at the individual level was assessed using the Reliable Change Index (RCI). Adolescents were classified as treatment responders if they achieved a reliable change in outcomes across time points and also demonstrated a change in clinical severity range in the expected direction (ie, from severe to moderate). RESULTS: Reliable and clinically significant improvements in pain-related fear and avoidance, functional disability, and school functioning were demonstrated at discharge, with improvements maintained at 3-month and 6-month follow-up. Among core outcomes, 48% (n=13) of patients were classified as treatment responders in one or more outcomes at discharge, with this increasing to 76% (n=19) at 3-month follow-up. DISCUSSION: Examining reliable and clinically meaningful change (vs. statistical significance alone) provides a way to examine treatment response to an intervention and to enhance the interpretability of findings, helping to bridge the gap between clinical trials and clinical practice by providing guidelines for interpretation.