Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma.

PURPOSE: About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL. PATIENTS AND METHODS: We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes. RESULTS: Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay. CONCLUSION: We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.

Long-term neurological dysfunction associated with COVID-19: Lessons from influenza and inflammatory diseases?

As the COVID-19 pandemic persists, SARS-CoV-2 infection is increasingly associated with long-term neurological side effects including cognitive impairment, fatigue, depression, and anxiety, colloquially known as "long-COVID." While the full extent of long-COVID neuropathology across years or even decades is not yet known, we can perhaps take direction from long-standing research into other respiratory diseases, such as influenza, that can present with similar long-term neurological consequences. In this review, we highlight commonalities in the neurological impacts of influenza and COVID-19. We first focus on the common potential mechanisms underlying neurological sequelae of long-COVID and influenza, namely (1) viral neurotropism and (2) dysregulated peripheral inflammation. The latter, namely heightened peripheral inflammation leading to central nervous system dysfunction, is emerging as a shared mechanism in various peripheral inflammatory or inflammation-associated diseases and conditions. We then discuss historical and modern examples of influenza- and COVID-19-associated cognitive impairment, depression, anxiety, and fatigue, revealing key similarities in their neurological sequelae. Although we are learning that the effects of influenza and COVID differ somewhat in terms of their influence on the brain, as the impacts of long-COVID grow, such comparisons will likely prove valuable in guiding ongoing research into long-COVID, and perhaps foreshadow what could be in store for individuals with COVID-19 and their brain health.

Comparative sequence analysis elucidates the evolutionary patterns of Yersinia pestis in New Mexico over thirty-two years.

Background: Yersinia pestis, a Gram-negative bacterium, is the causative agent of plague. Y. pestis is a zoonotic pathogen that occasionally infects humans and became endemic in the western United States after spreading from California in 1899. Methods: To better understand evolutionary patterns in Y. pestis from the southwestern United States, we sequenced and analyzed 22 novel genomes from New Mexico. Analytical methods included, assembly, multiple sequences alignment, phylogenetic tree reconstruction, genotype-phenotype correlation, and selection pressure. Results: We identified four genes, including Yscp and locus tag YPO3944, which contained codons undergoing negative selection. We also observed 42 nucleotide sites displaying a statistically significant skew in the observed residue distribution based on the year of isolation. Overall, the three genes with the most statistically significant variations that associated with metadata for these isolates were sapA, fliC, and argD. Phylogenetic analyses point to a single introduction of Y. pestis into the United States with two subsequent, independent movements into New Mexico. Taken together, these analyses shed light on the evolutionary history of this pathogen in the southwestern US over a focused time range and confirm a single origin and introduction into North America.

A tumor-restricted glycoform of podocalyxin is a highly selective marker of immunologically cold high-grade serous ovarian carcinoma.

Introduction: Targeted-immunotherapies such as antibody-drug conjugates (ADC), chimeric antigen receptor (CAR) T cells or bispecific T-cell engagers (eg, BiTE®) all aim to improve cancer treatment by directly targeting cancer cells while sparing healthy tissues. Success of these therapies requires tumor antigens that are abundantly expressed and, ideally, tumor specific. The CD34-related stem cell sialomucin, podocalyxin (PODXL), is a promising target as it is overexpressed on a variety of tumor types and its expression is consistently linked to poor prognosis. However, PODXL is also expressed in healthy tissues including kidney podocytes and endothelia. To circumvent this potential pitfall, we developed an antibody, named PODO447, that selectively targets a tumor-associated glycoform of PODXL. This tumor glycoepitope is expressed by 65% of high-grade serous ovarian carcinoma (HGSOC) tumors. Methods: In this study we characterize these PODO447-expressing tumors as a distinct subset of HGSOC using four different patient cohorts that include pre-chemotherapy, post-neoadjuvant chemotherapy (NACT) and relapsing tumors as well as tumors from various peritoneal locations. Results: We find that the PODO447 epitope expression is similar across tumor locations and negligibly impacted by chemotherapy. Invariably, tumors with high levels of the PODO447 epitope lack infiltrating CD8+ T cells and CD20+ B cells/plasma cells, an immune phenotype consistently associated with poor outcome. Discussion: We conclude that the PODO447 glycoepitope is an excellent biomarker of immune "cold" tumors and a candidate for the development of targeted-therapies for these hard-to-treat cancers.

Short- and Long-Term Outcomes of Hematologic Malignancy Patients After Cardiopulmonary Resuscitation: Experience of a Large Oncology Center.

PURPOSE: The objective of this study is to describe characteristics and short- and long-term outcomes of patients with hematologic malignancies who received cardiopulmonary resuscitation (CPR). METHODS: A retrospective review was conducted of all Code Blues at a large comprehensive cancer center. Demographic, clinical, and outcome variables were analyzed for patients with a hematologic malignancy who underwent CPR. RESULTS: Of 258 patients, 60.1% had leukemia. Outcomes included return of spontaneous circulation (70.2%), hospital survival (12%), and 90-day, 6-month, and 1-year survival rates of 9.8%, 8.2%, and 5.9%, respectively. Factors associated with hospital mortality included establishing a do not resuscitate order after CPR (p < .0001), location of CPR (p = .0004), cause of arrest (p = .0019), requiring vasopressors (p = .0130), mechanical ventilation (p = .0423), and acute renal failure post CPR (p = .0006). Although no difference in hospital survival between leukemia and non-leukemia patients was found, more non-leukemia patients were alive at 90 days (p = .0099), 6 months (p = .0023), and 1 year (p = .0119). CONCLUSIONS: Factors including organ dysfunction, location of CPR, and cause of arrest are associated with hospital mortality post CPR. However, immediate survival post CPR does not seem to be affected by a diagnosis of leukemia. These data should assist health care providers with discussions regarding advance care planning and goals of care after cardiac arrest.

Survey of Nurses' Experiences Applying The Joint Commission's Medication Management Titration Standards.

BACKGROUND: Critical care nurses titrate continuous infusions of medications to achieve clinical end points. In 2017, The Joint Commission (TJC) placed restrictions on titration practice, decreasing nurses' autonomous decision-making. OBJECTIVES: To describe the practice and perceptions of nurses regarding the 2017 TJC accreditation/regulatory standards for titration of continuous medication infusions. METHODS: A survey of nurses' experiences titrating continuous medication infusions was developed, validated, and distributed electronically to members of the American Association of Critical-Care Nurses. RESULTS: The content validity index for the survey was 1.0 for relevance and 0.95 for clarity. A total of 781 nurses completed the survey; 625 (80%) perceived titration standards to cause delays in patient care, and 726 (93%) experienced moral distress (mean [SD], 4.97 [2.67]; scale, 0-10). Among respondents, 33% could not comply with titration orders, 68% reported suboptimal care resulting from pressure to comply with orders, 70% deviated from orders to meet patient needs, and 84% requested revised orders to ensure compliance. Suboptimal care and delays in care significantly and strongly (regression coefficients ≥0.69) predicted moral distress. CONCLUSIONS: Critical care nurses perceive TJC medication titration standards to adversely impact patient care and contribute to moral distress. The improved 2020 updates to the standards do not address delays and inability to comply with orders, leading to moral distress. Advocacy is indicated in order to mitigate unintended consequences of TJC medication management titration standards.

Chlamydia Infection Among Adolescent Long-Acting Reversible Contraceptive and Shorter-Acting Hormonal Contraceptive Users Receiving Services at New York City School-Based Health Centers.

STUDY OBJECTIVE: One concern regarding long-acting reversible contraceptive (LARC) use among female adolescents is the potential for sexually transmitted infection acquisition. Few studies investigate chlamydia infection among adolescent LARC users compared with other hormonal contraceptive method (non-LARC) users. We hypothesized that incident chlamydia infection would be similar in these 2 groups and that it would not be associated with adolescent LARC use. DESIGN, SETTING, AND PARTICIPANTS: Secondary data analysis of electronic health records of adolescents who started using LARC (n = 152) and non-LARC methods (n = 297) at 6 New York City school-based health centers between March 2015 and March 2017. INTERVENTIONS AND MAIN OUTCOME MEASURES: Demographic characteristics, sexual risk factors, and occurrence of chlamydia infection over a period of 1 year were compared in the 2 groups using χ2 tests and t tests. Multivariable logistic regression was used to test the association between LARC use and chlamydia infection adjusting for relevant covariates. RESULTS: Among 422 adolescent patients tested the year after method initiation, 48 (11.4%) had at least 1 positive chlamydia test. The proportions of LARC users and non-LARC users with chlamydia infection were not statistically significantly different (10.9% vs 11.6%; P = .82). Multivariable analysis showed that LARC use was not associated with greater chlamydia risk (adjusted odds ratio, 0.84; 95% confidence interval, 0.41-1.43). CONCLUSION: Adolescent LARC users did not have significantly higher chlamydia infection occurrence compared with non-LARC users the year after method initiation. Concern for chlamydial infection should prompt recommending condom use but should not be a barrier to recommending adolescent LARC use.

Revised Self-Report Assessment of Functional Visual Performance (R-SRAFVP)-Part I: Content Validation.

OBJECTIVE: We describe the development and content validation of the revised Self-Report Assessment of Functional Visual Performance (R-SRAFVP). METHOD: The content validation process consisted of three stages: (1) three occupational therapy experts in low vision rehabilitation revised items on the 38-item SRAFVP via written feedback and semistructured interview, (2) eight occupational therapy low vision experts evaluated items for relevance and provided feedback on the rating scale, and (3) five adults with low vision provided feedback on item clarity via cognitive interviewing. RESULTS: In Stage 1 review, 21 items were added, totaling 59 items. In Stage 2 evaluation, 9 items were eliminated, resulting in the 50-item R-SRAFVP with a 4-point scale. The scale content validity index of the R-SRAFVP was .9. Stage 3 cognitive interviewing provided no substantive changes in content. CONCLUSION: R-SRAFVP content was relevant to evaluate the ability of adults with low vision to complete vision-dependent daily tasks and was understandable by these participants.

Revised Self-Report Assessment of Functional Visual Performance (R-SRAFVP)-Part II: Construct Validation.

OBJECTIVE: Our objective was to validate the construct of the Revised Self-Report Assessment of Functional Visual Performance (R-SRAFVP) for older adults with low vision resulting from age-related eye disease. METHOD: The 50-item draft of the R-SRAFVP was administered to 87 older adults with low vision. Construct validation included principal-components analysis and the known-groups method. RESULTS: Principal-components analysis revealed nine components (comprising 33 items): Personal Care, Oral Care, Meal/Laundry Preparation, Financial Management, Telephone Usage, Personal Preference Activities, Reading, Writing, and Functional Mobility. Cronbach's α ranged from .72 to .84 for individual components and was .92 overall. Known-groups comparisons showed that participants with moderate to profound acuity loss or contrast sensitivity deficits reported significantly greater difficulty completing tasks on the R-SRAFVP than those with milder acuity loss or normal contrast sensitivity. CONCLUSION: The 33-item R-SRAFVP demonstrates adequate evidence of reliability and validity to evaluate the ability of older adults with low vision to complete vision-dependent activities of daily living.

Health Literacy in Older Adults With and Without Low Vision.

OBJECTIVE: In this study, we investigated whether older adults with low vision (LV) from age-related macular degeneration (AMD) demonstrated lower functional health literacy than older adults without LV. METHOD: Fifty adults with AMD were matched with adults without LV on age, gender, education, and income. We measured visual acuity, contrast sensitivity, and reading speed and administered the Test of Functional Health Literacy in Adults (TOFHLA) using two test time conditions, standard and unlimited, to measure health literacy levels. RESULTS: The group with LV had considerably lower TOFHLA scores for both time conditions (p < .001) and took notably longer to complete the test (p < .001). Poorer acuity correlated with lower TOFHLA scores in the group with LV. CONCLUSION: Older adults with LV may take longer to read and understand health information, which has important implications for providing health education to support self-management. Modifying components of the reading task may facilitate reading performance and understanding of health education materials.

Validation of a Reading Assessment for Persons With Homonymous Hemianopia or Quadrantanopia.

OBJECTIVE: To preliminarily validate the Visual Skills for Reading Test (VSRT) for assessing reading performance in persons with homonymous hemianopia (HH) or quadrantanopia. DESIGN: Retrospective chart review. SETTING: University-based outpatient low vision rehabilitation center. PARTICIPANTS: Persons (N=38) with HH or quadrantanopia who completed the VSRT. INTERVENTIONS: Validation procedures included testing for equivalence of the 3 test versions, estimation of internal consistency reliability, and known-group comparison using VSRT results from previous studies of adults with normal vision and central field loss. MAIN OUTCOME MEASURES: Corrected reading rate, reading accuracy rate, type and number of reading errors, and completion time were recorded and evaluated. RESULTS: Cronbach α for the VSRT across all participants was .80, which indicated good internal consistency. A known-group comparison showed that persons with a visual field deficit read significantly slower than did normally sighted adults (t580=10.13; P<.0001). Persons with quadrantanopia read significantly faster than did persons with HH (t36=2.25; P=.03) or those with central field loss (t48=3.17; P=.0027). These findings confirmed that the VSRT correctly discriminated between groups in terms of reading performance. CONCLUSIONS: Preliminary validation results indicate that the VSRT demonstrates adequate evidence of reliability and validity to evaluate reading performance in adults with HH or quadrantanopia.

Prevalence of pediatric epilepsy in low-income rural Midwestern counties.

Epilepsy is one of the most common disabling neurological disorders, but significant gaps exist in our knowledge about childhood epilepsy in rural populations. The present study assessed the prevalence of pediatric epilepsy in nine low-income rural counties in the Midwestern United States overall and by gender, age, etiology, seizure type, and syndrome. Multiple sources of case identification were used, including medical records, schools, community agencies, and family interviews. The prevalence of active epilepsy was 5.0/1000. Prevalence was 5.1/1000 in males and 5.0/1000 in females. Differences by age group and gender were not statistically significant. Future research should focus on methods of increasing study participation in rural communities, particularly those in which research studies are rare.

Client and therapist perspectives on the influence of low vision and chronic conditions on performance and occupational therapy intervention.

OBJECTIVE: We explored how vision loss and comorbid chronic conditions influence occupational therapy intervention by gathering perspectives from occupational therapists treating clients with low vision and from older adults with low vision. METHOD: We surveyed 59 occupational therapists on the frequency of comorbidities in their clients and their influence on low vision intervention. Eight older adults with low vision participated in in-depth interviews and observations on the influence of low vision and comorbidities on their occupational performance. Conclusions reflect data analysis from both methods. RESULTS: The occupational therapists modified low vision interventions to address the added effect of each comorbidity. Modifications included more treatment sessions, home visits, referrals to other professions, and provision of strategies to address comorbidities. The older adults viewed vision loss as a stronger influence than comorbidities on independence in daily occupations. CONCLUSION: Both vision loss and comorbidities influence occupational performance, supporting the need for interventions to address both conditions.

Exploring the impact of a pre-service interprofessional educational intervention for school mental health trainees.

With collaborative interprofessional teams integral to school mental health (SMH) service delivery, pre-service educational strategies are needed to promote interprofessional collaboration among SMH trainees. The current study evaluated the effectiveness, feasibility, and acceptability of a pre-service, interprofessional SMH educational intervention focused on promoting the cross-disciplinary competencies essential for SMH practice. Eight SMH trainees participated in the study. Using a mixed-method design, quantitative pre/post competency data were collected via trainee self-report. Qualitative data were collected through a focus group and reflection journals. Results indicate that the intervention promoted competency in all areas, with significant growth in the provision of learning supports to youth. Key factors influencing intervention feasibility included time/scheduling, changing school team composition, and project coordination. Trainees' perceptions of the educational intervention were related to buy-in, clinical experience, and role flexibility. Implications for the design of pre-service interprofessional SMH education strategies are discussed.

Visual concerns that interfere with daily activities in patients on rehabilitation units: a descriptive study.

The purpose of this study was to estimate the prevalence of patients with visual concerns that interfere with their activities of daily living (ADL) performance in physical rehabilitation units through occupational therapy assessment. Over the two-month study period, 215 adult inpatients from a physical rehabilitation hospital were evaluated using the Brief Vision Screen (BVS) through ADL. The BVS assessed four areas of visual concerns, namely left visual field, focusing, and near- and low-contrast acuity, while patients engaged in ADL. The occupational therapists identified 33% of patients who had at least one area of visual concern, with the largest proportion diagnosed with stroke (55%), followed by pulmonary disease (40%) and joint replacement (35%). When comparing the four areas of visual concerns in the BVS between the two major diagnostic groups (acquired brain injury, ABI and non-acquired brain injury, non-ABI), a significantly higher proportion of patients with ABI were identified as having left hemianopsia concerns compared to patients with non-ABI. No significant difference was observed in other areas of visual concern between the two groups. Findings indicated that visual concerns that interfere with ADL performance among older patients in rehabilitation units are common. The high proportion of patients with pulmonary disease identified as having visual concerns warranted further confirmation and investigation. Preliminary evidence to support the psychometric properties of the BVS for identifying visual concerns in patients on rehabilitation units was established.

Assessment of the visual status of older adults on an orthopedic unit.

PURPOSE. To examine the visual status of a cohort of older adults on an orthopedic unit to determine their level of available vision to complete everyday activities in the hospital setting. METHOD. A convenience sample of 50 people was recruited. A visual history was obtained, and participants' glasses were inspected. Distance acuity, reading acuity, and contrast sensitivity were assessed using standardized screening charts. RESULTS. Of participants, 26% did not have their glasses with them until prompted, and 85% had glasses in poor condition. When tested wearing their habitual correction, 6% had low vision, 2% were blind, 41% had reading acuities worse than 20/25, and 28% had contrast sensitivity deficits. CONCLUSION. Visual impairment is prevalent in older adults, yet visual function is not routinely screened in hospitals. Occupational therapists should routinely inquire about patients' visual status, inspect their glasses, and encourage regular eye examinations. Failure to address vision could lead to inaccurate evaluation results.

Clinical application of low vision rehabilitation strategies after completion of a computer-based training module.

This study evaluated changes in occupational therapists' practice behaviors after completion of an online continuing education (CE) program delivered over a hospital Intranet system. The setting was a large rural medical system covering parts of two southeastern states. A convenience sample of 28 occupational therapists and occupational therapy assistants was recruited from the facility therapy staff. A CE module on low vision assessment and treatment was delivered using the hospital Intranet and a follow-up survey assessing practice change was carried out 8 weeks later. Most participants reported an increase in their comfort level when treating clients with low vision after course completion. Fifty percent of participants reported screening for vision impairments, increased use of environmental modifications, and more referrals to other vision specialists. Outcomes suggest that Internet-delivered CE programs can improve knowledge and affect practice.

Effects of leptin replacement therapy on pancreatic ß-cell function in patients with lipodystrophy.

OBJECTIVE Leptin administration is known to directly modulate pancreatic ß-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on ß-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on ß-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on ß-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. ß-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, ß-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on ß-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or ß-cell function in leptin-deficient individuals with lipodystrophy.

Factors associated with comfort level of occupational therapy practitioners in providing low vision services.

OBJECTIVE. We describe the perceived adequacy of educational preparation for and comfort level of occupational therapy practitioners in providing services to clients with low vision and identify factors associated with the practitioners' comfort level. METHOD. One hundred occupational therapists who were not specialists in low vision rehabilitation completed a survey. RESULTS. Fifty-two percent of the respondents perceived that they had received adequate preparation in occupational therapy school to address low vision. Between 54% and 63% of respondents were comfortable performing visual screening and providing interventions for clients with low vision. Multivariable analyses indicated that having received adequate preparation in occupational therapy school, having a partnership with an eye-care professional, and having provided services to a larger percentage of clients with low vision were significantly associated with perceived comfort in providing services to this population. CONCLUSION. Findings provide an initial direction to improve low vision content in occupational therapy education curricula.