Machine learning prediction of pathological complete response and overall survival of breast cancer patients in an underserved inner-city population.

BACKGROUND: Generalizability of predictive models for pathological complete response (pCR) and overall survival (OS) in breast cancer patients requires diverse datasets. This study employed four machine learning models to predict pCR and OS up to 7.5 years using data from a diverse and underserved inner-city population. METHODS: Demographics, staging, tumor subtypes, income, insurance status, and data from radiology reports were obtained from 475 breast cancer patients on neoadjuvant chemotherapy in an inner-city health system (01/01/2012 to 12/31/2021). Logistic regression, Neural Network, Random Forest, and Gradient Boosted Regression models were used to predict outcomes (pCR and OS) with fivefold cross validation. RESULTS: pCR was not associated with age, race, ethnicity, tumor staging, Nottingham grade, income, and insurance status (p > 0.05). ER-/HER2+ showed the highest pCR rate, followed by triple negative, ER+/HER2+, and ER+/HER2- (all p < 0.05), tumor size (p < 0.003) and background parenchymal enhancement (BPE) (p < 0.01). Machine learning models ranked ER+/HER2-, ER-/HER2+, tumor size, and BPE as top predictors of pCR (AUC = 0.74-0.76). OS was associated with race, pCR status, tumor subtype, and insurance status (p < 0.05), but not ethnicity and incomes (p > 0.05). Machine learning models ranked tumor stage, pCR, nodal stage, and triple-negative subtype as top predictors of OS (AUC = 0.83-0.85). When grouping race and ethnicity by tumor subtypes, neither OS nor pCR were different due to race and ethnicity for each tumor subtype (p > 0.05). CONCLUSION: Tumor subtypes and imaging characteristics were top predictors of pCR in our inner-city population. Insurance status, race, tumor subtypes and pCR were associated with OS. Machine learning models accurately predicted pCR and OS.

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

Spatiotemporal Live-Cell Analysis of Photoreceptor Outer Segment Membrane Ingestion by the Retinal Pigment Epithelium Reveals Actin-Regulated Scission.

The photoreceptor outer segment (OS) is the phototransductive organelle in the vertebrate retina. OS tips are regularly ingested and degraded by the adjacent retinal pigment epithelium (RPE), offsetting the addition of new disk membrane at the base of the OS. This catabolic role of the RPE is essential for photoreceptor health, with defects in ingestion or degradation underlying different forms of retinal degeneration and blindness. Although proteins required for OS tip ingestion have been identified, spatiotemporal analysis of the ingestion process in live RPE cells is lacking; hence, the literature reflects no common understanding of the cellular mechanisms that affect ingestion. We imaged live RPE cells from mice (both sexes) to elucidate the ingestion events in real time. Our imaging revealed roles for f-actin dynamics and specific dynamic localizations of two BAR (Bin-Amphiphysin-Rvs) proteins, FBP17 and AMPH1-BAR, in shaping the RPE apical membrane as it surrounds the OS tip. Completion of ingestion was observed to occur by scission of the OS tip from the remainder of the OS, with a transient concentration of f-actin forming around the site of imminent scission. Actin dynamics were also required for regulating the size of the ingested OS tip, and the time course of the overall ingestion process. The size of the ingested tip is consistent with the term "phagocytosis." However, phagocytosis usually refers to engulfment of an entire particle or cell, whereas our observations of OS tip scission indicate a process that is more specifically described as "trogocytosis," in which one cell "nibbles" another cell.SIGNIFICANCE STATEMENT The ingestion of the photoreceptor outer segment (OS) tips by the retinal pigment epithelium (RPE) is a dynamic cellular process that has fascinated scientists for 60 years. Yet its molecular mechanisms had not been addressed in living cells. We developed a live-cell imaging approach to investigate OS tip ingestion, and focused on the dynamic participation of actin filaments and membrane-shaping BAR proteins. We observed scission of OS tips for the first time, and were able to monitor local changes in protein concentration preceding, during, and following scission. Our approach revealed that actin filaments were concentrated at the site of OS scission and were required for regulating the size of the ingested OS tip and the time course of the ingestion process.

A Smartphone App for Parental Management of Adolescent Conduct Problems: Randomized Clinical Trial of iKinnect.

OBJECTIVE: This study evaluates iKinnect, a linked caregiver-teen mobile app system designed to address serious adolescent conduct problems through a focus on key targets of evidence-based treatments for juvenile offending, such as parent expectation setting, monitoring, consistency, and positive reinforcement. Additional gamification and autonomy-supporting features are designed to maximize youth engagement. Digital therapeutics such as mobile apps have great potential to expand access to effective interventions, particularly for youth who engage in serious conduct problems and substance abuse, since most never receive an evidence-based treatment and few apps exist for these concerns. METHODS: This randomized clinical trial used a short-term (12 week) longitudinal design with four time points. Recruited was a U.S. national sample of teens (n = 72, age 13-17, 59.7% male, 68.1% White) receiving services for a serious conduct problem and their primary caregiver. The efficacy of iKinnect, used by parent and teen dyads, was measured against an active control condition, Life360, an app that provided mutual GPS-based location tracking to dyads. RESULTS: Across 12 weeks of app use, youth who used iKinnect showed significantly greater reductions in alcohol use, marijuana use, school delinquency, status offenses, and general delinquency than did controls. Parents who used iKinnect Reported greater improvements in structure/rule clarity and discipline consistency relative to control parents. Teen and parent iKinnect app use and acceptability ratings were high. CONCLUSIONS: Real-world use of iKinnect in future applications can, like other emerging digital health technologies, help to expand the reach of evidence-based interventions to children, youth, and families.Registered at clinicaltrials.gov (NCT03065517).

Breast cancer survivorship care during the COVID-19 pandemic within an urban New York Hospital System.

PURPOSE: To examine clinicodemographic determinants associated with breast cancer survivorship follow-up during COVID-19. METHODS: We performed a retrospective, population-based cohort study including early stage (Stage I-II) breast cancer patients who underwent resection between 2006 and 2018 in a New York City hospital system. The primary outcome was oncologic follow-up prior to and during the COVID-19 pandemic. Secondary analyses compared differences in follow-up by COVID-19 case rates stratified by ZIP code. RESULTS: A total of 2942 patients with early-stage breast cancer were available for analysis. 1588 (54%) of patients had attended follow-up in the year prior to the COVID-19 period but failed to continue to follow-up during the pandemic, either in-person or via telemedicine. 1242 (42%) patients attended a follow-up appointment during the COVID-19 pandemic. Compared with patients who did not present for follow-up during COVID-19, patients who continued their oncologic follow-up during the pandemic were younger (p = 0.049) more likely to have received adjuvant radiation therapy (p = 0.025), and have lower household income (p = 0.031) on multivariate modeling. When patients who live in Bronx, New York, were stratified by ZIP code, there was a modest negative association (r = -0.56) between COVID-19 cases and proportion of patients who continued to follow-up during the COVID-19 period. CONCLUSION: We observed a dramatic disruption in routine breast cancer follow-up during the COVID-19 pandemic. Providers and health systems should emphasize reintegrating patients who missed appointments during COVID-19 back into regular surveillance programs to avoid significant morbidity and mortality from missed breast cancer recurrences.

Mapping the discursive dimensions of the reproducibility crisis: A mixed methods analysis.

To those involved in discussions about rigor, reproducibility, and replication in science, conversation about the "reproducibility crisis" appear ill-structured. Seemingly very different issues concerning the purity of reagents, accessibility of computational code, or misaligned incentives in academic research writ large are all collected up under this label. Prior work has attempted to address this problem by creating analytical definitions of reproducibility. We take a novel empirical, mixed methods approach to understanding variation in reproducibility discussions, using a combination of grounded theory and correspondence analysis to examine how a variety of authors narrate the story of the reproducibility crisis. Contrary to expectations, this analysis demonstrates that there is a clear thematic core to reproducibility discussions, centered on the incentive structure of science, the transparency of methods and data, and the need to reform academic publishing. However, we also identify three clusters of discussion that are distinct from the main body of articles: one focused on reagents, another on statistical methods, and a final cluster focused on the heterogeneity of the natural world. Although there are discursive differences between scientific and popular articles, we find no strong differences in how scientists and journalists write about the reproducibility crisis. Our findings demonstrate the value of using qualitative methods to identify the bounds and features of reproducibility discourse, and identify distinct vocabularies and constituencies that reformers should engage with to promote change.

Usability Evaluation for Evidence-Based Psychosocial Interventions (USE-EBPI): A methodology for assessing complex intervention implementability.

Background: Most evidence-based practices in mental health are complex psychosocial interventions, but little research has focused on assessing and addressing the characteristics of these interventions, such as design quality and packaging, that serve as intra-intervention determinants (i.e., barriers and facilitators) of implementation outcomes. Usability-the extent to which a product can be used by specified users to achieve specified goals with effectiveness, efficiency, and satisfaction-is a key indicator of design quality. Drawing from the field of human-centered design, this article presents a novel methodology for evaluating the usability of complex psychosocial interventions and describes an example "use case" application to an exposure protocol for the treatment of anxiety disorders with one user group. Method: The Usability Evaluation for Evidence-Based Psychosocial Interventions (USE-EBPI) methodology comprises four steps: (1) identify users for testing; (2) define and prioritize EBPI components (i.e., tasks and packaging); (3) plan and conduct the evaluation; and (4) organize and prioritize usability issues. In the example, clinicians were selected for testing from among the identified user groups of the exposure protocol (e.g., clients, system administrators). Clinicians with differing levels of experience with exposure therapies (novice, n =3; intermediate, n = 4; advanced, n = 3) were sampled. Usability evaluation included Intervention Usability Scale (IUS) ratings and individual user testing sessions with clinicians, and heuristic evaluations conducted by design experts. After testing, discrete usability issues were organized within the User Action Framework (UAF) and prioritized via independent ratings (1-3 scale) by members of the research team. Results: Average IUS ratings (80.5; SD = 9.56 on a 100-point scale) indicated good usability and also room for improvement. Ratings for novice and intermediate participants were comparable (77.5), with higher ratings for advanced users (87.5). Heuristic evaluations suggested similar usability (mean overall rating = 7.33; SD = 0.58 on a 10-point scale). Testing with individual users revealed 13 distinct usability issues, which reflected all four phases of the UAF and a range of priority levels. Conclusion: Findings from the current study suggested the USE-EBPI is useful for evaluating the usability of complex psychosocial interventions and informing subsequent intervention redesign (in the context of broader development frameworks) to enhance implementation. Future research goals are discussed, which include applying USE-EBPI with a broader range of interventions and user groups (e.g., clients). Plain language abstract: Characteristics of evidence-based psychosocial interventions (EBPIs) that impact the extent to which they can be implemented in real world mental health service settings have received far less attention than the characteristics of individuals (e.g., clinicians) or settings (e.g., community mental health centers), where EBPI implementation occurs. No methods exist to evaluate the usability of EBPIs, which can be a critical barrier or facilitator of implementation success. The current article describes a new method, the Usability Evaluation for Evidence-Based Psychosocial Interventions (USE-EBPI), which uses techniques drawn from the field of human-centered design to evaluate EBPI usability. An example application to an intervention protocol for anxiety problems among adults is included to illustrate the value of the new approach.

A novel engagement of suicidality in the emergency department: Virtual Collaborative Assessment and Management of Suicidality.

OBJECTIVE: A novel avatar system (Virtual Collaborative Assessment and Management of Suicidality System; V-CAMS) for suicidal patients and medical personnel in emergency departments (EDs) was developed and evaluated. V-CAMS facilitates the delivery of CAMS and other evidence-based interventions to reduce unnecessary hospitalization, readmissions, and suicide following an ED visit. METHOD: Using iterative user-centered design with 24 suicidal patients, an avatar prototype, "Dr. Dave" (based on Dr. Jobes) was created, along with other patient-facing tools; provider-facing tools, including a clinical decision support tool were also designed and tested to aid discharge disposition. RESULTS: Feasibility tests supported proof of concept. Suicidal patients affirmed the system's overall merit, positive Perception of Care, and acceptability; medical providers (n = 21) viewed the system as an efficient, effective, and safe method of improving care for suicidal ED patients and reducing unnecessary hospitalization. CONCLUSIONS: Technology tools including a patient-facing avatar and e-caring contacts, along with provider-facing tools may offer a powerful method of facilitating best-practice suicide prevention interventions and point-of-care tools for suicidal patients seeking ED services and their medical providers. Future directions include full development of V-CAMS and integration into a health electronic medical record and a rigorous randomized controlled trial to study its effectiveness.

An Interscholastic Network To Generate LexA Enhancer Trap Lines in Drosophila.

Binary expression systems like the LexA-LexAop system provide a powerful experimental tool kit to study gene and tissue function in developmental biology, neurobiology, and physiology. However, the number of well-defined LexA enhancer trap insertions remains limited. In this study, we present the molecular characterization and initial tissue expression analysis of nearly 100 novel StanEx LexA enhancer traps, derived from the StanEx1 index line. This includes 76 insertions into novel, distinct gene loci not previously associated with enhancer traps or targeted LexA constructs. Additionally, our studies revealed evidence for selective transposase-dependent replacement of a previously-undetected KP element on chromosome III within the StanEx1 genetic background during hybrid dysgenesis, suggesting a molecular basis for the over-representation of LexA insertions at the NK7.1 locus in our screen. Production and characterization of novel fly lines were performed by students and teachers in experiment-based genetics classes within a geographically diverse network of public and independent high schools. Thus, unique partnerships between secondary schools and university-based programs have produced and characterized novel genetic and molecular resources in Drosophila for open-source distribution, and provide paradigms for development of science education through experience-based pedagogy.

Effectiveness of adaptive seating on sitting posture and postural control in children with cerebral palsy.

PURPOSE: We reviewed research on the effect of adaptive seating on sitting posture/postural control in children with cerebral palsy. Second, we examined whether changes in postural control related to changes in other aspects of functioning. METHODS: Electronic database/hand searches were undertaken to locate studies published in English. Reviewers screened studies for inclusion criteria, extracted data, indexed outcomes to the International Classification of Functioning, Disability and Health, assigned levels of evidence, and assessed study quality. RESULTS: Thirteen of 14 articles used group designs and the other a single-subject design. Conflicting findings were reported for saddle seats and optimal seat/back angle for improving sitting posture/postural control. Significant improvements were reported with seat inserts, external supports, and modular seating systems. Evidence supporting effects of postural control on functional abilities was limited. CONCLUSIONS: Future studies on the effects of adaptive seating should describe participants with standardized classification systems and employ stronger research designs.

A mouse Fcgamma-Fcepsilon protein that inhibits mast cells through activation of FcgammaRIIB, SH2 domain-containing inositol phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases.

BACKGROUND: A human Fcgamma-Fcepsilon fusion protein (GE2) designed to inhibit FcepsilonRI signaling by coaggregating FcepsilonRI with the inhibitory receptor FcgammaRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcgammaRIIB. OBJECTIVE: Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. METHODS: The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow-derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum-sensitized cynomolgus monkeys. RESULTS: mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcgammaRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcgammaRIIB phosphorylation and the subsequent recruitment of SH2 domain-containing inositol polyphosphate 5' phosphatase (SHIP) 1 and SH2 domain-containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. CONCLUSION: mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcgammaRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.

An intermediate pH unfolding transition abrogates the ability of IgE to interact with its high affinity receptor FcepsilonRIalpha.

The interaction between IgE-Fc (Fcepsilon) and its high affinity receptor FcepsilonRI on the surface of mast cells and basophils is a key event in allergen-induced allergic inflammation. Recently, several therapeutic strategies have been developed based on this interaction, and some include Fcepsilon-containing moieties. Unlike well characterized IgG therapeutics, the stability and folding properties of IgE are not well understood. Here, we present comparative biophysical analyses of the pH stability and thermostability of Fcepsilon and IgG1-Fc (Fcgamma). Fcepsilon was found to be significantly less stable than Fcgamma under all pH and NaCl conditions tested. Additionally, the Cepsilon3Cepsilon4 domains of Fcepsilon were shown to become intrinsically unfolded at pH values below 5.0. The interaction between Fcepsilon and an Fcgamma-FcepsilonRIalpha fusion protein was studied between pH 4.5 and 7.4 using circular dichroism and a combination of differential scanning calorimetry and isothermal titration calorimetry. Under neutral pH conditions, the apparent affinity of Fcepsilon for the dimeric fusion protein was extremely high compared with published values for the monomeric receptor (KD < 10(-12) m). Titration to pH 6.0 did not significantly change the binding affinity, and titration to pH 5.5 only modestly attenuated affinity. At pH values below 5.0, the receptor binding domains of Fcepsilon unfolded, and interaction of Fcepsilon with the Fcgamma-FcepsilonRIalpha fusion protein was abrogated. The unusual pH sensitivity of Fcepsilon may play a role in antigen-dependent regulation of receptor-bound, non-circulating IgE.