Financial assistance and other financial coping strategies after a pediatric cancer diagnosis.

BACKGROUND: Families experience financial burden and household material hardship (HMH) after a pediatric cancer diagnosis. This study investigates types of financial assistance and other financial coping strategies (FCS) adopted by families during the first year after diagnosis. METHODS: Retrospective survey of caregivers of pediatric patients diagnosed with cancer from 2015 to 2019. The survey collected data on demographics, diagnosis, income, HMH, and private, hospital, and government assistance received and other FCS adopted after diagnosis. Bivariate and multivariable logistic regressions were used to analyze FCS by income. Subgroup analysis of families experiencing HMH was used to identify predictors of receiving government assistance. RESULTS: Of 156 respondents, 52% were low-to-middle income, 29% had public insurance, and 22% had non-English language preference. Low-to-middle-income families were more likely to incur debt (odds ratio [OR] 6.24, p < .001) and reduce consumption (OR 2.16, p = .03) than high-income families, and this association persisted in multivariable analysis. Among families with housing, food, and energy insecurity, 40%, 70%, and 39%, respectively, received hospital or government assistance specific to the experienced hardship. In subgroup analysis of families with HMH, after adjusting for income and other confounders, non-English language preference was associated with lower odds of receiving government assistance. CONCLUSIONS: After a pediatric cancer diagnosis, low-to-middle-income families are more likely to incur debt than high-income families. Most families experiencing food insecurity received some food assistance, while housing and energy assistance were less common. Future studies should investigate methods to equitably improve access to financial assistance and minimize long-term financial consequences.

Disparities in household material hardship, financial toxicity, and income loss in pediatric cancer.

BACKGROUND: Based on previous reports of disparities in financial burden following a cancer diagnosis, this study aims to characterize mechanisms of disparities experienced by caregivers of children with cancer, including the impact of work flexibility and social support. METHODS: Cross-sectional survey (in English or Spanish) of caregivers of children with cancer that assessed household material hardship (HMH), financial toxicity, and income change. RESULTS: Of 156 caregivers surveyed, 32% were Hispanic and 32% were low income. Hispanic caregivers were more likely to report HMH and financial toxicity compared to non-Hispanic White and Asian (HMH: 57% vs. 21% vs. 19%, p < .001; financial toxicity: 73% vs. 52% vs. 53%, p = .07). Low- and middle-income caregivers were more likely to experience HMH and financial toxicity compared to high-income caregivers (HMH: 68% low vs. 38% middle vs. 8.7% high, p < .001; financial toxicity: 81% vs. 68% vs. 44%, p < .001). All income categories demonstrated significant increases in HMH 1 year after diagnosis. Seventeen percent reported more than 40% income loss, more of whom were low income than high income (27% vs. 12%, p = .20). Work flexibility and social support were associated with income and financial toxicity. CONCLUSION: HMH, financial toxicity, and income loss are prevalent after a child's cancer diagnosis, suggesting that screening should be incorporated into routine care. This financial burden disproportionately affects low-income and Hispanic caregivers. Further research is needed to elucidate the roles of work flexibility and social support, how safety net services are utilized by families, and how best to support families with HMH.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

Factors that contribute to disparities in time to acute leukemia diagnosis in young people: an in depth qualitative interview study.

BACKGROUND: Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. METHODS: This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family's experiences preceding the patient's diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. RESULTS: Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers' management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. CONCLUSIONS: While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

Educating Certified Nursing Assistants to Communicate Skin Changes to Reduce Pressure Injuries.

Pressure injuries (PIs) are common and costly complications in long-term care (LTC) residents. Educating and coaching certified nursing assistants (CNAs) to communicate early skin changes is a PI surveillance strategy that may influence PI outcomes. A communication guide related to Skin, Clean, Activity, and Nutrition was developed for CNAs to promote prompt upstream communication to licensed nurses. A pre-/post-intervention design measured PI knowledge and skills in 24 CNAs, and PI incidence was tracked over a 6-week time period. CNAs demonstrated improvement in their PI surveillance role, comfort in identifying and reporting skin changes, keeping skin clean and dry, and resident nutritional status. Baseline PI incidence of 9.6% decreased to 0% by Week 3, and no new PIs occurred over 6 weeks. CNAs developed role awareness and knowledge in primary PI surveillance and were instrumental in a team approach to decrease PIs in a LTC setting. [Journal of Gerontological Nursing, 47(8), 21-28.].

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial.

BACKGROUND: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). METHODS: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. FINDINGS: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2-25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2-24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). INTERPRETATION: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. FUNDING: Blueprint Medicines.

Patients' Experiences with Telecare for Chronic Pain and Mood Symptoms: A Qualitative Study.

OBJECTIVE: Pain, anxiety, and depression commonly co-occur, can have reciprocal effects, and are associated with substantial disability and health care costs. However, few interventions target treatment of pain and mood disorders as a whole. The Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) trial was a randomized trial comparing two pragmatic telecare interventions, a high- vs low-resource approach to pain and anxiety/depression treatment. The purpose of the current study is to better understand patients' perspectives on both intervention approaches, including intervention components, delivery, patient experiences, and patient outcomes. DESIGN: Qualitative, semistructured interviews. SETTING: A Veterans Affairs Medical Center. SUBJECTS: Twenty-five patients were purposefully sampled from both study arms. METHODS: Patients were interviewed about their experiences with pain and mood treatment, perceived benefits and changes, and experiences with the intervention model to which they were randomized. The constant comparison method guided analysis. RESULTS: Pain was more important than mood for most participants. Participants described developing increased awareness of their symptoms, including connecting pain and mood, which enabled better management. Participants in the high-resource intervention described the added value of the study nurse in their symptom management. CONCLUSIONS: Patients in a telecare intervention for chronic pain and mood symptoms learned to connect pain and mood and be more aware of their symptoms, enabling more effective symptom management. Patients in the high-resource intervention described the added benefits of a nurse who provided informational and motivational support. Implications for tradeoffs between resource intensity and patient outcomes are discussed.

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

Automated Self-management (ASM) vs. ASM-Enhanced Collaborative Care for Chronic Pain and Mood Symptoms: the CAMMPS Randomized Clinical Trial.

BACKGROUND: Chronic musculoskeletal pain is often accompanied by depression or anxiety wherein co-occurring pain and mood symptoms can be more difficult to treat than either alone. However, few clinical trials have examined interventions that simultaneously target both pain and mood conditions. OBJECTIVE: To determine the comparative effectiveness of automated self-management (ASM) vs. ASM-enhanced collaborative care. DESIGN: Randomized clinical trial conducted in six primary care clinics in a VA medical center. PARTICIPANTS: Two hundred ninety-four patients with chronic musculoskeletal pain of at least moderate intensity and clinically significant depressive and/or anxiety symptoms. INTERVENTION: ASM consisted of automated monitoring and 9 web-based self-management modules. Comprehensive symptom management (CSM) combined ASM with collaborative care management by a nurse-physician team. Both interventions were delivered for 12 months. MAIN MEASURES: Primary outcome was a composite pain-anxiety-depression (PAD) z-score consisting of the mean of the BPI, PHQ-9, and GAD-7 z-scores: 0.2, 0.5, and 0.8 represent potentially small, moderate, and large clinical differences. Secondary outcomes included global improvement, health-related quality of life, treatment satisfaction, and health services use. KEY RESULTS: Both CSM and ASM groups had moderate PAD score improvement at 12 months (z = - 0.65 and - 0.52, respectively). Compared to the ASM group, the CSM group had a - 0.23 (95% CI, - 0.38 to - 0.08; overall P = .003) greater decline in composite PAD z-score over 12 months. CSM patients were also more likely to report global improvement and less likely to report worsening at 6 (P = .004) and 12 months (P = .013). CONCLUSIONS: Two intervention models relying heavily on telecare delivery but differing in resource intensity both produced moderate improvements in pain and mood symptoms. However, the model combining collaborative care led by a nurse-physician team with web-based self-management was superior to self-management alone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT0175730.

The Tec Kinase-Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages.

Previous work has shown conflicting roles for Tec family kinases in regulation of TLR-dependent signaling in myeloid cells. In the present study, we performed a detailed investigation of the role of the Tec kinases Btk and Tec kinases in regulating TLR signaling in several types of primary murine macrophages. We demonstrate that primary resident peritoneal macrophages deficient for Btk and Tec secrete less proinflammatory cytokines in response to TLR stimulation than do wild-type cells. In contrast, we found that bone marrow-derived and thioglycollate-elicited peritoneal macrophages deficient for Btk and Tec secrete more proinflammatory cytokines than do wild-type cells. We then compared the phosphoproteome regulated by Tec kinases and LPS in primary peritoneal and bone marrow-derived macrophages. From this analysis we determined that Tec kinases regulate different signaling programs in these cell types. In additional studies using bone marrow-derived macrophages, we found that Tec and Btk promote phosphorylation events necessary for immunoreceptor-mediated inhibition of TLR signaling. Taken together, our results are consistent with a model where Tec kinases (Btk, Tec, Bmx) are required for TLR-dependent signaling in many types of myeloid cells. However, our data also support a cell type-specific TLR inhibitory role for Btk and Tec that is mediated by immunoreceptor activation and signaling via PI3K.

Reducing disparities in behavioral health treatment in pediatric primary care: a randomized controlled trial comparing Partnering to Achieve School Success (PASS) to usual ADHD care for children ages 5 to 11 - study protocol.

BACKGROUND: Integrating behavioral health services into pediatric primary care can improve access to care, especially for children marginalized by poverty and racial/ethnic minority status. In primary care, a common presenting concern is attention-deficit/hyperactivity disorder (ADHD). Services in primary care for marginalized children with ADHD typically include medication alone; therapy to improve skills and build relationships is less available. This study evaluates the effectiveness of a behavioral intervention offered through primary care for marginalized families coping with ADHD (Partnering to Achieve School Success, PASS) compared to treatment as usual (TAU). METHOD: Three hundred participants will be randomly assigned to PASS or TAU. Participants include children ages 5 to 11 who have ADHD and are from economically marginalized families. PASS is a personalized, enhanced behavioral intervention that includes evidence-based behavior therapy strategies and enhancements to promote family engagement, increase caregiver distress tolerance, and provide team-based care to improve academic and behavioral functioning. TAU includes services offered by primary care providers and referral for integrated behavioral health or community mental health services. Outcomes will be assessed at mid-treatment (8 weeks after baseline), post-treatment (16 weeks), and follow-up (32 weeks) using parent- and teacher-report measures of service use, child academic, behavioral, and social functioning, parenting practices, family empowerment, and team-based care. Mixed effects models will examine between-group differences at post-treatment and follow-up. Analyses will examine the mediating role of parenting practices, family empowerment, and team-based care. Subgroup analyses will examine differential effects of intervention by child clinical characteristics and socioeconomic factors. DISCUSSION: This study is unique in targeting a population of children with ADHD marginalized by low socioeconomic resources and examining an intervention designed to address the challenges of families coping with chronic stress related to poverty. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov (NCT04082234) on September 5, 2019, prior to enrollment of the first participant. The current version of the protocol and IRB approval date is October 4, 2023. Results will be submitted to ClinicalTrials.gov no later than 30 days prior to the due date for the submission of the draft of the final research report to the Patient-Centered Outcomes Research Institute.

A miniaturized wash-free microfluidic assay for electrical impedance-based assessment of red blood cell-mediated microvascular occlusion.

The production of HbS - an abnormal hemoglobin (Hb) - in sickle cell disease (SCD) results in poorly deformable red blood cells (RBCs) that are prone to microcapillary occlusion, causing tissue ischemia and organ damage. Novel treatments, including gene therapy, may reduce SCD morbidity, but methods to functionally evaluate RBCs remain limited. Previously, we presented the microfluidic impedance red cell assay (MIRCA) for rapid assessment of RBC deformability, employing electrical impedance-based readout to measure RBC occlusion of progressively narrowing micropillar openings. We describe herein the design, development, validation, and clinical utility of the next-generation MIRCA assay, featuring enhanced portability, rapidity, and usability. It incorporates a miniaturized impedance analyzer and features a simplified wash-free operation that yields an occlusion index (OI) within 15 min as a new metric for RBC occlusion. We show a correlation between OI and percent fetal hemoglobin (%HbF), other laboratory biomarkers of RBC hemolysis, and SCD severity. To demonstrate the assay's versatility, we tested RBC samples from treatment-naïve SCD patients in Uganda that yielded OI levels similar to those from hydroxyurea (HU)-treated patients in the U.S., highlighting the role of %HbF in protecting against microcapillary occlusion independent of other pharmacological effects. The MIRCA assay could also identify a subset of HU-treated patients with high occlusion risks, suggesting that they may require treatment adjustments including a second-line therapy to improve their outcomes. This work demonstrates the potential of the MIRCA assay for accelerated evaluation of RBC health, function, and therapeutic effect in an ex vivo model of the microcapillary networks.

Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans.

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

iCLOTS: open-source, artificial intelligence-enabled software for analyses of blood cells in microfluidic and microscopy-based assays.

While microscopy-based cellular assays, including microfluidics, have significantly advanced over the last several decades, there has not been concurrent development of widely-accessible techniques to analyze time-dependent microscopy data incorporating phenomena such as fluid flow and dynamic cell adhesion. As such, experimentalists typically rely on error-prone and time-consuming manual analysis, resulting in lost resolution and missed opportunities for innovative metrics. We present a user-adaptable toolkit packaged into the open-source, standalone Interactive Cellular assay Labeled Observation and Tracking Software (iCLOTS). We benchmark cell adhesion, single-cell tracking, velocity profile, and multiscale microfluidic-centric applications with blood samples, the prototypical biofluid specimen. Moreover, machine learning algorithms characterize previously imperceptible data groupings from numerical outputs. Free to download/use, iCLOTS addresses a need for a field stymied by a lack of analytical tools for innovative, physiologically-relevant assays of any design, democratizing use of well-validated algorithms for all end-user biomedical researchers who would benefit from advanced computational methods.

Therapist-Delivered Versus Care Ally-Assisted Massage for Veterans With Chronic Neck Pain: Protocol for a Randomized Controlled Trial.

BACKGROUND: Chronic neck pain (CNP) is prevalent, and it reduces functional status and quality of life and is associated with deleterious psychological outcomes in affected individuals. Despite the desirability of massage and its demonstrated effectiveness in CNP treatment, multiple accessibility barriers exist. Caregiver-applied massage has demonstrated feasibility in various populations but has not been examined in Veterans with CNP or compared in parallel to therapist-delivered massage. OBJECTIVE: This manuscript described the original study design, lessons learned, and resultant design modifications for the Trial Outcomes for Massage: Care Ally-Assisted Versus Therapist-Treated (TOMCATT) study. METHODS: TOMCATT began as a 3-arm, randomized controlled trial of 2 massage delivery approaches for Veterans with CNP with measures collected at baseline, 1 and 3 months after intervention, and 6 months (follow-up). Arm I, care ally-assisted massage, consisted of an in-person, 3.5-hour training workshop, an instructional DVD, a printed treatment manual, and three 30-minute at-home care ally-assisted massage sessions weekly for 3 months. Arm II, therapist-treated massage, consisted of two 60-minute sessions tailored to individual pain experiences and treatments per week for 3 months. The treatments followed a standardized Swedish massage approach. Arm III consisted of wait-list control. RESULTS: Retention and engagement challenges in the first 30 months were significant in the care ally-assisted massage study arm (63% attrition between randomization and treatment initiation) and prompted modification to a 2-arm trial, that is, removing arm I. CONCLUSIONS: The modified TOMCATT study successfully launched and exceeded recruitment goals 2.5 months before the necessary COVID-19 pause and is expected to be completed by early 2023. TRIAL REGISTRATION: ClinicalTrials.gov NCT03100539; https://clinicaltrials.gov/ct2/show/NCT03100539. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38950.

PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development.

The Ets transcription factor PU.1 is essential for inducing the differentiation of monocytes, macrophages, and B cells in fetal liver and adult bone marrow. PU.1 controls hematopoietic differentiation through physical interactions with other transcription factors, such as C/EBPα and the AP-1 family member c-Jun. We found that PU.1 recruits c-Jun to promoters without the AP-1 binding sites. To address the functional importance of this interaction, we generated PU.1 point mutants that do not bind c-Jun while maintaining normal DNA binding affinity. These mutants lost the ability to transactivate a target reporter that requires a physical PU.1-c-Jun interaction, and did not induce monocyte/macrophage differentiation of PU.1-deficient cells. Knock-in mice carrying these point mutations displayed an almost complete block in hematopoiesis and perinatal lethality. While the PU.1 mutants were expressed in hematopoietic stem and early progenitor cells, myeloid differentiation was severely blocked, leading to an almost complete loss of mature hematopoietic cells. Differentiation into mature macrophages could be restored by expressing PU.1 mutant fused to c-Jun, demonstrating that a physical PU.1-c-Jun interaction is crucial for the transactivation of PU.1 target genes required for myeloid commitment and normal PU.1 function in vivo during macrophage differentiation.

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

Improved efficacy of a tolerizing DNA vaccine for reversal of hyperglycemia through enhancement of gene expression and localization to intracellular sites.

Insulin is a major target for the autoimmune-mediated destruction of pancreatic beta cells during the pathogenesis of type I diabetes. A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mouse model of type I diabetes when administered to hyperglycemic (therapeutic mode) or normoglycemic (prophylactic mode) NOD mice. Therapeutic administration of proinsulin DNA was accompanied by a rapid decrease in the number of insulin-specific IFN-gamma-producing T cells, whereas prophylactic treatment was accompanied by enhanced IFN-gamma-secreting cells and a decrease in insulin autoantibodies. Adoptive transfer experiments demonstrated that the protection was not mediated by induction of CD25(+)/CD4(+) T regulatory cells. The efficacy of the DNA vaccine was enhanced by increasing the level of expression of the encoded Ag, more frequent dosing, increasing dose level, and localization of the protein product to the intracellular compartment. The efficacy data presented in this study demonstrate that Ag-specific plasmid DNA therapy is a viable strategy for preventing progression of type I diabetes and defines critical parameters of the dosing regime that influences tolerance induction.

Telecare management of pain and mood symptoms: Adherence, utility, and patient satisfaction.

INTRODUCTION: Pain, depression, and anxiety are prominent symptoms that frequently co-occur, causing significant debilitation and frequent primary care visits. This paper examines the acceptability of telecare and self-management modules in managing these conditions in a randomized trial. METHODS: The Comprehensive Management of Mood and Physical Symptoms (CAMMPS) trial compared an automated symptom management (ASM) plus self-management intervention with a comprehensive symptom management (CSM) intervention that added telecare facilitation of enhanced services. Data from the CAMMPS trial were analysed to compare the acceptability of these two interventions as indicated by utilization and patient satisfaction surveys. RESULTS: The mean number of automated reports completed was similar between the CSM and ASM groups (14.5 vs 14.0). Responses designated with clinically relevant "red alerts" (i.e. patient reports warranting an expedited nurse contact) were more frequent in the CSM group (10.2 vs 8.3). The CSM and ASM groups completed a similar number of the nine self-management modules (6.3 vs 5.8). The mean helpfulness score across all modules was higher in the CSM group than in the ASM group (1.8 vs 1.5; p = .003). The most common feedback suggestion from the ASM group was to have more personal interaction, while participants from both groups commonly suggested technical improvements or requests for more flexible timing of calls. DISCUSSION: Participants generally found both interventions satisfactory, with a trend in satisfaction data suggesting that patients tended to find the CSM intervention more helpful.

Autonomic Cross-Innervation in Patients With Neurofibromatosis Type 2: Frey Syndrome and Unilateral Epiphora With Rhinorrhea.

The authors present 2 cases of cross-innervation in patients with neurofibromatosis type 2. In the first case, an iodine test was performed to demonstrate Frey syndrome in a 28-year-old female with neurofibromatosis type 2 who developed symptoms at age 10 years. The second patient is an 18-year-old female with neurofibromatosis type 2, 2 years status post left vestibular schwannoma subtotal resection who presented with paradoxical unilateral lacrimation and rhinorrhea triggered by heat stress and exercise. The pathophysiology of these cases is discussed.