An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Can Genomic Testing Help Refine Choosing Wisely the Omission of Axillary Staging in cN0 Breast Cancer?

INTRODUCTION: Choosing Wisely (CW) recommends women age ≥70 y with cT1-2cN0 ER+/HER2-invasive breast cancer (BC) should forgo routine axillary staging with sentinel lymph node biopsy (SLN) at the time of breast surgery. Despite this longstanding recommendation, acceptance of SLN omission has not been widely adopted. Genomic assays, such as MammaPrint (MP), may supplement the decision to apply CW. We hypothesized that having MP on BC core needle biopsy (CNB) meeting CW could provide additional information to aid in decision-making about the need for axillary staging with SLN. METHODS: A retrospective single-institution review was conducted for women with BC meeting CW criteria, who also had MP performed on CNB from 2020 to 2021. Categorical characteristics were compared using the chi-square test. Continuous variables were compared using the Mann-Whitney U-test. RESULTS: MP was available on CNB for 238 BC meeting CW criteria: 70% low risk and 30% high risk. Axillary staging was performed in 195 (82%). Eighty-one percent were pathologically node-negative and 19% were pathologically node-positive. The MP score did not correlate with pathologic nodal stage (P = 0.52). The rate of high nodal burden (pN2) was extremely low (n = 1, 0.5%). The only significant correlation with pathological node positivity was older age (P = 0.03). Appropriately, high-risk MP was strongly associated with increased recurrence risk (n = 4, P = 0.008). CONCLUSIONS: Having MP on CNB does not provide clinically meaningful information about the pN stage and does not further refine which BC patients within CW could benefit from escalation to SLN or delineate a group more likely to be pathologically node-negative.

The Availability of Allergen-Friendly Food for College Students Experiencing Food Insecurity: Exploring Current Campus Practices.

BACKGROUND: The burden of dietary restrictions includes the high cost and limited availability of allergen-friendly products which disproportionately impacts people with food insecurity. OBJECTIVE: We aimed to better understand access to allergen-friendly food college students experiencing food-insecurity with food allergies or other diet-treated conditions by surveying college campus food pantries. METHODS: 120 randomly selected United States colleges/universities were recruited to complete FOODiversity's Food Insecurity Questionnaire about campus food pantry operations, dietary restrictions, and food-insecurity initiatives, and provide details about their resources and training dedicated to supporting food-insecure young adults who avoid a specific food(s). RESULTS: Forty-eight percent of respondents ask students about dietary restrictions at food pantry intake, 37% track the number of patrons with restrictions, 30% process allergen-friendly product requests, 17% train staff about dietary restrictions, and 4% modify processes to accommodate dietary restrictions. Of the 48% who inquire about dietary restrictions, follow-up interventions vary in levels of accommodation. Dairy-free and gluten-free products are most commonly requested, and gluten-free products are the most donated/stocked and most difficult to accommodate. CONCLUSION: Food pantries play a critical role in reducing the burden experienced by food-insecure individuals, however, most pantries are unable to provide sufficient accommodations for clients with food allergies or other diet-treated conditions, including staff training, provision of allergen-friendly products, or identifying food-insecure college students with dietary restrictions; and promoting food allergy safety and nutritional impacts.

The role of spirituality in pain experiences among adults with cancer: an explanatory sequential mixed methods study.

PURPOSE: Foundational research demonstrates that spirituality may affect the way people with cancer experience pain. One potential route is through alterations in thoughts and beliefs, such as pain-related catastrophizing. The purpose of this study is to understand whether spirituality impacts pain experiences through pain-related catastrophizing. METHODS: This explanatory sequential mixed methods study was informed by an adapted Theory of Unpleasant Symptoms. Data were collected via online surveys (N = 79) and follow-up qualitative interviews (N = 25). Phase 1 employed Empirical Bayesian analysis. Phase 2 used deductive content analysis. Phase 3 involved creating a mixed methods joint display to integrate findings and draw meta inferences. RESULTS: Results indicate that total spiritual well-being was directly negatively associated with pain-related catastrophizing, and indirectly negatively associated with the outcomes of pain interference, pain severity, and pain-related distress. Qualitative categories highlight the supportive role of spirituality when facing pain, while also shedding light on the limitations of spirituality in the context of some pain (i.e., severe, neuropathic, and/or chronic). Mixed methods findings reveal the importance of spirituality for some people as they face cancer and cancer-related pain, as well as the need for integrating spirituality as part of a larger pain management plan. CONCLUSIONS: This research advances supportive cancer care by exploring the complex role of spirituality in pain experiences. Findings will inform further exploration into the role of spirituality in supporting holistic symptom management in the context of cancer, as well as developing and testing interventions to enhance spirituality and address symptom-related suffering.

Perceived injustice and pain-related outcomes in children with pain conditions: A systematic review.

OBJECTIVE: Research indicates that perceived injustice significantly influences pain-related outcomes and is associated with delayed recovery in adults. This systematic review examines the relationship between perceived injustice and pain-related outcomes in children with pain conditions. METHODS: A search of published studies in English in PubMed, PsychInfo and Cochrane Database of Systematic Reviews from database inception through December 2022 was performed. The search criteria focused on studies that measured perceived injustice and pain-related outcomes in children with pain conditions. Out of 56 articles screened, 8 met the inclusion criteria, providing data on 1240 children with pain conditions. RESULTS: The average age of participants across all studies was 14.12 years (SD = 2.25), with 68.2% being female. There was strong evidence that higher perceived injustice is associated with worse pain intensity, functional disability, mental health outcomes, and emotional, social and school functioning. CONCLUSION: The results of this study underscore how perceptions of injustice are associated various pain-related outcomes across different domains of children's lives. The findings highlight the need for screening and treatments targeting injustice appraisals in pediatric populations with pain conditions. The discussion addresses possible determinants and mechanisms of perceived injustice, along with implications for research and clinical practice.

The Impact of a Student-Led Health Education Clinic on the Health Literacy and Behaviors of a Rural Community in the State of Pennsylvania, USA.

Rural populations experience a number of disparities that place them at increased risk of morbidity and mortality related to chronic disease, including lower health literacy and greater distance to medical care. Community-based free healthcare education can offer targeted preventive care to these vulnerable populations; however, limited quantitative research exists measuring their impact, specifically on health literacy and likelihood for behavior change. To investigate this, a student-led health education clinic was held in January 2023 in the rural community of Lykens, Pennsylvania by the Student-run and Collaborative Outreach Program for Health Equity (SCOPE). Fifty-five pre- and post-clinic surveys using Likert-style questions measured the knowledge and likelihood of behavioral change for several preventive health topics, including hypertension, diabetes mellitus, cancer screenings, childhood vaccinations, skin cancer, mental health, addiction, and nutrition. From pre- to post-clinic, there was a significant increase in knowledge of hypertension (p = 0.023) and diabetes (p = 0.014), likelihood of attending cancer screenings (p = 0.038), and confidence in identifying cancerous moles (p = < 0.001). There was a non-significant increase in understanding of mental health and nutrition, and no change in understanding of addiction or childhood vaccinations. It is likely that the level of interaction in education provided and relevance of information to participants contributed to effective uptake of information. The results demonstrate an immediate impact on health literacy and likelihood of behavioral change for several important preventive health topics, and advocate for the use of student-run healthcare interventions in addressing the prevalence of chronic disease in rural communities.

The Impact of Age, Sex, and Position on Visual-Motor Processing Speed and Reaction Time as Measured by the Vision CoachTM.

Occupational therapists are in a unique position to screen and evaluate fitness to drive with both visual-motor processing speed and reaction time being important factors to consider when determining fitness to drive. This study uses the Vision CoachTM to investigate the differences in visual-motor processing speed and reaction time across age and sex of healthy adults. It also explores whether the position of sitting or standing made any difference. The results showed no difference between male/female or standing/sitting positions. However, there was a statistically significant difference between age groups, with older adults demonstrating slower visual-motor processing speed and reaction times. These findings can be used for future studies to explore the impact of injury or disease on visual-motor processing speed and reaction times and its relation to fitness to drive.

Elusive hypersomnolence in seasonal affective disorder: actigraphic and self-reported sleep in and out of depressive episodes.

BACKGROUND: Hypersomnolence has been considered a prominent feature of seasonal affective disorder (SAD) despite mixed research findings. In the largest multi-season study conducted to date, we aimed to clarify the nature and extent of hypersomnolence in SAD using multiple measurements during winter depressive episodes and summer remission. METHODS: Sleep measurements assessed in individuals with SAD and nonseasonal, never-depressed controls included actigraphy, daily sleep diaries, retrospective self-report questionnaires, and self-reported hypersomnia assessed via clinical interviews. To characterize hypersomnolence in SAD we (1) compared sleep between diagnostic groups and seasons, (2) examined correlates of self-reported hypersomnia in SAD, and (3) assessed agreement between commonly used measurement modalities. RESULTS: In winter compared to summer, individuals with SAD (n = 64) reported sleeping 72 min longer based on clinical interviews (p < 0.001) and 23 min longer based on actigraphy (p = 0.011). Controls (n = 80) did not differ across seasons. There were no seasonal or group differences on total sleep time when assessed by sleep diaries or retrospective self-reports (p's > 0.05). Endorsement of winter hypersomnia in SAD participants was predicted by greater fatigue, total sleep time, time in bed, naps, and later sleep midpoints (p's < 0.05). CONCLUSION: Despite a winter increase in total sleep time and year-round elevated daytime sleepiness, the average total sleep time (7 h) suggest hypersomnolence is a poor characterization of SAD. Importantly, self-reported hypersomnia captures multiple sleep disruptions, not solely lengthened sleep duration. We recommend using a multimodal assessment of hypersomnolence in mood disorders prior to sleep intervention.

Safety of guselkumab treatment for up to 5†years in patients with moderate-to-severe psoriasis: pooled analyses across seven clinical trials with more than 8600 patient-years of exposure.

BACKGROUND: Guselkumab has demonstrated favourable safety and efficacy across individual clinical studies in adults with moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the safety of guselkumab in patients with psoriasis using pooled data from seven phase II/III studies (X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan registration). METHODS: All studies, except NAVIGATE and ECLIPSE (active comparator-controlled only), included a 16-week placebo-controlled period; X-PLORE, VOYAGE 1 and VOYAGE 2 included both placebo and active controls. In most studies, guselkumab-treated patients received 100-mg subcutaneous injections at week 0, week 4, and then every 8 weeks thereafter. Safety data were summarized for the placebo-controlled period (weeks 0-16) and through the end of the reporting period (up to 5 years). Incidence rates of key safety events were integrated post hoc, adjusted for the duration of follow-up and reported per 100 patient-years (PY). RESULTS: During the placebo-controlled period, 544 patients received placebo (165 PY) and 1220 received guselkumab (378 PY). Through the end of the reporting period, 2891 guselkumab-treated patients contributed 8662 PY of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of adverse events (AEs) were 346/100 PY and 341/100 PY, and infections were 95.9/100 PY and 83.6/100 PY. Rates of serious AEs (6.3/100 PY vs. 6.7/100 PY), AEs leading to discontinuation (5.0/100 PY vs. 9.7/100 PY), serious infections (1.1/100 PY vs. 1.2/100 PY), malignancy (0.5 patients/100 PY vs. 0.0 patients/100 PY) and major adverse cardiovascular events (MACE; 0.3/100 PY vs. 0.0/100 PY) were low and comparable between guselkumab and placebo. Through the end of the reporting period, safety event rates were lower than or comparable to the placebo-controlled period in guselkumab-treated patients: AEs, 169/100 PY; infections, 65.9/100 PY; serious AEs, 5.3/100 PY; AEs leading to discontinuation, 1.6/100 PY; serious infections, 0.9/100 PY; malignancy, 0.7/100 PY; and MACE, 0.3/100 PY. There were no cases of Crohn disease, ulcerative colitis, opportunistic infection or active tuberculosis related to guselkumab. CONCLUSIONS: In this comprehensive analysis of 2891 guselkumab-treated patients with psoriasis followed for up to 5 years (8662 PY), guselkumab demonstrated favourable safety, consistent with previous reports. Safety event rates in guselkumab-treated patients were similar to those observed with placebo and were consistent throughout long-term treatment.

Validation of the PREDICT Prognostication Tool in US Patients With Breast Cancer.

BACKGROUND: PREDICT is an online prognostication tool derived from breast cancer registry information on approximately 6,000 women treated in the United Kingdom that estimates the postsurgical treatment benefit of surgery alone, chemotherapy, trastuzumab, endocrine therapy, and/or adjuvant bisphosphonates in early-stage breast cancer. Our aim was to validate the PREDICT algorithm in predicting 5- and 10-year overall survival (OS) probabilities using real-world outcomes among US patients with breast cancer. METHODS: A retrospective study was performed including women diagnosed with unilateral breast cancer in 2004 through 2012. Women with primary unilateral invasive breast cancer were included. Patients with bilateral or metastatic breast cancer, no breast surgery, or missing critical clinical information were excluded. Prognostic scores from PREDICT were calculated and external validity was approached by assessing statistical discrimination through area under time-dependent receiver-operator curves (AUC) and comparing the predicted survival to the observed OS in relevant subgroups. RESULTS: We included 708,652 women, with a median age of 58 years. Most patients were White (85.4%), non-Hispanic (88.4%), and diagnosed with estrogen receptor-positive breast cancer (79.6%). Approximately 50% of patients received adjuvant chemotherapy, 67% received adjuvant endocrine therapy, 60% underwent a partial mastectomy, and 59% had 1 to 5 axillary sentinel nodes removed. Median follow-up time was 97.7 months. The population's 5- and 10-year OS were 89.7% and 78.7%, respectively. Estimated 5- and 10-year median survival with PREDICT were 88.3% and 73.8%, and an AUC of 0.77 and 0.76, respectively. PREDICT performed most poorly in patients with high Charlson-Deyo comorbidity scores (2-3), where PREDICT overestimated OS. Sensitivity analysis by year of diagnosis and HER2 status showed similar results. CONCLUSIONS: In this prognostic study utilizing the National Cancer Database, the PREDICT tool accurately predicted 5- and 10-year OS in a contemporary and diverse population of US patients with nonmetastatic breast cancer.

Modeling the COVID Pandemic: Do Delays in Surgery Justify Using Stereotactic Radiation to Treat Low-Risk Early Stage Non-Small Cell Lung Cancer?

INTRODUCTION: It was suggested that stereotactic radiation (SBRT) is an "alternative if no surgical capacity is available" for non-small cell lung cancer (NSCLC) care during the COVID-19 pandemic. The purpose of this study was to compare the oncologic outcomes of delayed surgical resection and early SBRT among operable patients with early stage lung cancer. METHODS: The National Cancer Database was queried for patients with cT1aN0M0 NSCLC who underwent surgery or SBRT (2010-2016) with no comorbidity. Patients with any comorbidities or age >80 were excluded. The outcome of interest was overall survival. Delays in surgical care were modeled using different times from diagnosis to surgery. A 1:1 propensity match was performed and survival was analyzed using multivariable Cox regression. RESULTS: Of 6720 healthy cT1aN0M0 NSCLC patients, 6008 (89.4%) received surgery and 712 (10.6%) received SBRT. Among surgery patients, time to surgery >30 d was associated with inferior survival (HR > 1.4, P ≤ 0.013) compared with patients receiving surgery ≤14 d. Relative to SBRT, surgery demonstrated superior survival at all time points evaluated: 0-30 d, 31-60 d, 61-90 d, and >90 d (all P < 0.001). Among a propensity-matched cohort of 256 pairs of patients, delayed surgery (>90 d) remained association with better overall survival relative to early SBRT (5-year survival 76.9% versus 32.3%, HR = 0.266, P < 0.001). CONCLUSIONS: Although longer time to surgery is associated with inferior survival among surgery patients, delayed surgery is superior to early SBRT. Surgical resection should remain the standard of care to treat operable early stage lung cancer despite delays imposed by the COVID-19 pandemic.

Racial-ethnic variations in phyllodes tumors among a multicenter United States cohort.

BACKGROUND AND OBJECTIVES: Previous studies have identified racial-ethnic differences in the diagnostic patterns and recurrence outcomes of women with phyllodes tumors (PT). However, these studies are generally limited in size and generalizability. We therefore sought to explore racial-ethnic differences in age, tumor size, subtype, and recurrence in a large US cohort of women with PT. METHODS: We performed an 11-institution retrospective review of women with PT from 2007 to 2017. Differences in age at diagnosis, tumor size and subtype, and recurrence-free survival according to race-ethnicity. RESULTS: Women of non-White race or Hispanic ethnicity were younger at the time of diagnosis with phyllodes tumor. Non-Hispanic Other women had a larger proportion of malignant PT. There were no differences in recurrence-free survival in our cohort. CONCLUSIONS: Differences in age, tumor size, and subtype were small. Therefore, the workup of young women with breast masses and the treatment of women with PT should not differ according to race-ethnicity. These conclusions are supported by our finding that there were no differences in recurrence-free survival.

Food elimination diet is a viable alternative therapy for eosinophilic esophagitis responsive to proton pump inhibitors.

BACKGROUND: First-line treatment of eosinophilic esophagitis (EoE) includes monotherapy with proton-pump inhibitors (PPIs), food elimination diet (FED), or topical corticosteroids. Current guidelines suggest patients with EoE should continue any responsive first-line monotherapies. However, the efficacy of FED monotherapy in patients with EoE responsive to PPI monotherapy has not been well studied. Our study aimed to investigate how attempting FED monotherapy after experiencing remission of EoE after PPI monotherapy influenced long-term EoE management. METHODS: We retrospectively identified patients with EoE responsive to PPI monotherapy who trialed FED monotherapy. We then employed a mixed method approach to a prospective cohort. Selected patients were observed long term for quantitative outcomes, while qualitative results were obtained from patient surveys regarding their perspectives on the trial of FED monotherapy. RESULTS: We identified 22 patients who trialed FED monotherapy after experiencing remission of EoE following PPI monotherapy. Of these 22 patients, 13 had remission of EoE with FED monotherapy, while 9 had re-activation of EoE. Out of 22 patients, 15 were enrolled in a cohort for observation. No exacerbations of EoE occurred while on maintenance treatment. Most patients stated that they would recommend this process to others with EoE (93.33%) and that trial of FED monotherapy helped them identify a treatment plan that aligned with their lifestyle (80%). CONCLUSION: Our work shows that FED monotherapy can be an effective alternative for patients with EoE responsive to PPI monotherapy that may improve patient quality of life, suggesting alternative treatment options should be considered for monotherapy-responsive EoE.

Malignancy rates through 5 years of follow-up in patients with moderate-to-severe psoriasis treated with guselkumab: Pooled results from the VOYAGE 1 and VOYAGE 2 trials.

BACKGROUND: Malignancy risk surveillance among patients receiving long-term immunomodulatory psoriasis treatments remains an important safety objective. OBJECTIVE: To report malignancy rates in patients with moderate-to-severe psoriasis treated with guselkumab for up to 5 years versus general and psoriasis patient populations. METHODS: Cumulative rates of malignancies/100 patient-years (PY) were evaluated in 1721 guselkumab-treated patients from VOYAGE 1 and 2. Malignancy rates (excluding nonmelanoma skin cancer [NMSC]) were compared with rates in the Psoriasis Longitudinal Assessment and Registry. Standardized incidence ratios comparing malignancy rates (excluding NMSC and cervical cancer in situ) between guselkumab-treated patients and the general US population using Surveillance, Epidemiology, and End Results data were calculated, adjusting for age, sex, and race. RESULTS: Of 1721 guselkumab-treated patients (>7100 PY), 24 had NMSC (0.34/100PY; basal:squamous cell carcinoma ratio, 2.2:1), and 32 had malignancies excluding NMSC (0.45/100PY). For comparison, the malignancy rate excluding NMSC was 0.68/100PY in the Psoriasis Longitudinal Assessment and Registry. Malignancy rates (excluding NMSC/cervical cancer in situ) in guselkumab-treated patients were consistent with those expected in the general US population (standardized incidence ratio = 0.93). LIMITATIONS: Inherent imprecision in determining malignancy rates. CONCLUSIONS: In patients treated with guselkumab for up to 5 years, malignancy rates were low and generally consistent with rates in general and psoriasis patient populations.

The Pain and PRAYER Scale (PPRAYERS): development and validation of a scale to measure pain-related prayer.

OBJECTIVES: Prayer is a devotional practice used across religious traditions to commune with the sacred and has been used as a coping strategy for pain. Previous research on prayer as a pain coping strategy has had mixed results, with prayer associated with both greater and lesser pain depending on prayer type. To date, there has been only 1 measure of pain-related prayer, the prayer subscale of the Coping Strategies Questionnaire-Revised, which measures solely passive prayer, neglecting other types of prayer (eg, active and neutral). To better understand the relationship between pain and prayer, a comprehensive measure of prayer for pain is needed. The aim of this study was to develop and validate the Pain-related PRAYER Scale (PPRAYERS), a questionnaire exploring active, passive, and neutral petitionary prayers to God or a higher power in response to pain. METHODS: Adults with chronic pain (n = 411) completed demographic, health, and pain-related questionnaires, including PPRAYERS. RESULTS: Results of an exploratory factor analysis yielded a 3-factor structure consistent with active, passive, and neutral subscales. A confirmatory factor analysis resulted in adequate fit after the removal of 5 items. PPRAYERS showed good internal consistency and convergent and discriminant validity. DISCUSSION: These results provide preliminary validation for PPRAYERS, a novel measure for pain-related prayer.

Guselkumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa: A phase 2 randomized study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that causes substantial physical, emotional and psychological burdens. Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin-23, has demonstrated high levels of efficacy in the treatment of inflammatory diseases, including psoriasis and psoriatic arthritis. OBJECTIVE: To evaluate the effect of guselkumab on the treatment of HS, a phase 2, multicentre, randomized, placebo-controlled, double-blind, proof-of-concept study was conducted. METHODS: Patients ≥18 years of age with moderate-to-severe HS for ≥1 year were randomized to (1) guselkumab 200 mg by subcutaneous (SC) injection every 4 weeks (q4w) through Week 36 (guselkumab SC); (2) guselkumab 1200 mg intravenously (IV) q4w for 12 weeks, then switched to guselkumab 200 mg SC q4w from Weeks 12 through 36 (guselkumab IV); or (3) placebo for 12 weeks, with re-randomization to guselkumab 200 mg SC q4w at Weeks 16 through 36 (placebo → guselkumab 200 mg) or guselkumab 100 mg SC at Weeks 16, 20, 28 and 36 and placebo at Weeks 24 and 32 (placebo → guselkumab 100 mg). End points included HS clinical response (HiSCR) and patient-reported outcomes. RESULTS: Although guselkumab SC or guselkumab IV resulted in numerically higher HiSCR versus placebo at Week 16 (50.8%, 45.0%, 38.7%, respectively), statistical significance was not achieved. Numerically greater improvements in patient-reported outcomes were also observed for guselkumab SC and guselkumab IV versus placebo at Week 16. Through Week 40, no clear differences to suggest a dose response were observed for HiSCR and patient-reported outcomes. CONCLUSIONS: Despite modest improvements, the primary end point was not met and the overall findings do not support the efficacy of guselkumab in the treatment of HS. CLINICALTRIALS: gov: NCT03628924.

Experiences of medical traumatic stress in parents of children with medical complexity.

BACKGROUND AND OBJECTIVES: Parents of children with medical complexity (CMC) experience high levels of stress and adverse mental health outcomes. Pediatric medical traumatic stress (PMTS) could be an important contributor that has not yet been explored. PMTS describes parents' reactions to their child's illness and medical treatment and can lead to post-traumatic stress symptoms. This is the first study to describe the experiences and impact of PMTS among parents of CMC. METHODS: We conducted semi-structured interviews with 22 parents of CMC. Reflexive thematic analysis was used to generate themes that described the experiences of PMTS and potential contributing factors in the healthcare setting. Themes were validated by study participants. RESULTS: Parents experienced a spectrum of events and circumstances that impacted PMTS. These corresponded to three major themes: (a) the distinctive context of being the parent of a CMC, (b) interactions with healthcare providers that can hurt or heal and (c) system factors that set the stage for trauma. The consequences of repeated PMTS were a common point of emphasis among all the themes. Parents identified numerous changes that could mitigate PMTS such as acknowledgement of trauma and provision of proactive mental health support. CONCLUSIONS: Our study highlights the issue of PMTS among parents of CMC and presents opportunities to mitigate their traumatic experiences. Supporting the integration of trauma-informed care practices, increasing awareness of PMTS and advocating for parental mental health services could better support parents and families.

FoxO4 controls sGCß transcription in vascular smooth muscle.

Nitric oxide (NO) binds soluble guanylyl cyclase ß (sGCß) to produce cGMP and relax vascular smooth muscle cells (SMCs) needed for vasodilation. Although the regulation of NO-stimulated sGC activity has been well characterized at the posttranslational level, the mechanisms that govern sGC transcription remain incompletely understood. Recently, we identified Forkhead box subclass O (FoxO) transcription factors as essential for expression of sGC; however, the specific FoxO family member responsible for the expression of sGCß in SMC remains unknown. Using FoxO shRNA knockdown adenovirus treatment in rat aortic SMCs, we show that FoxO1 or FoxO3 knockdown causes greater than twofold increases in Gucy1a3 and Gucy1b3 mRNA expression, without changes in NO-dependent cGMP production or cGMP-dependent phosphorylation. FoxO4 knockdown produced a 50% decrease in Gucy1a3 and Gucy1b3 mRNA with 70% loss of sGCα and 50% loss of sGCß protein expression. Knockdown of FoxO4 expression decreased cGMP production and downstream protein kinase G-dependent phosphorylation more than 50%. Triple FoxO knockdown exacerbated loss of sGC-dependent function, phenocopying previous FoxO inhibition studies. Using promoter luciferase and chromatin immunoprecipitation assays, we find that FoxO4 acts as a transcriptional activator by directly binding several FoxO DNA motifs in the promoter regions of GUCY1B3 in human aortic SMCs. Collectively, our data show FoxO4 is a critical transcriptional regulator of sGCß expression in SMC.NEW & NOTEWORTHY One of the key mechanisms of vascular smooth muscle cell (SMC) dilation occurs through nitric oxide (NO)-dependent induction of soluble guanylyl cyclase (sGC) by means of its ß-subunit. Herein, we are the first to identify Forkhead box subclass O protein 4 (FoxO4) as a key transcriptional regulator of GUCY1B3 expression, which codes for sGCß protein in human and animal SMCs. This discovery will likely have important implications for the future usage of antihypertensive and vasodilatory therapies which target NO production, sGC, or FoxO transcription factors.

Adjuvant trastuzumab with or without chemotherapy in stage 1 pT1N0 HER2+ breast cancer: a National Cancer Database analysis.

PURPOSE: Approximately 20% of all breast cancers (BC) are HER2 amplified. In the APT trial, weekly paclitaxel/trastuzumab in node negative HER2+ BC with tumors < 3 cm was associated with a 7-year invasive disease-free survival of 93%. However, this was in the context of a non-randomized trial, and for pT1N0 HER2+ BC it remains unclear whether HER2 monotherapy would provide similar clinical outcomes to chemo-HER2 therapy. We hypothesized that adjuvant chemo-HER2 therapy would be associated with a modestly improved overall survival compared to HER2 monotherapy in patients with tumors < 2 cm. METHODS: In the National Cancer Database (2004-2017), patients with a primary diagnosis of pT1N0M0 HER2+ BC, were separated into two groups: (i) HER2 monotherapy, i.e., trastuzumab, and (ii) chemo-HER2 therapy. A 3:1 propensity match was performed to balance patient selection bias between the two different cohorts. Long-term overall survival (OS) was compared between both groups. RESULTS: A total of 23,281 patients met the criteria. 22,268 (96.7%) received chemo-HER2 therapy and 1013 (4.4%) received HER2 monotherapy. Propensity match identified 1995 patients who received chemo-HER2 therapy, and 666 who received HER2 monotherapy. After matching, adjuvant chemo-HER2 therapy was associated with a modest survival advantage over HER2 monotherapy (5-year OS 94.1% vs. 90.6%, P = 0.041). CONCLUSIONS: Even though there is a modest OS advantage favoring adjuvant chemo-HER2 therapy in patients with pT1N0 HER2+ BC, HER2 monotherapy was associated with 5-year OS > 90%. Therefore, in select patients who have contraindications for cytotoxic chemotherapy, or decline adjuvant chemotherapy altogether, adjuvant trastuzumab monotherapy appears to be a reasonable alternative.

Guideline-Consistent Treatment for Inflammatory Breast Cancer Provides Associated Survival Benefit Independent of Age.

BACKGROUND: Guideline-consistent treatment (GCT) for inflammatory breast cancer (IBC) includes neoadjuvant chemotherapy (NAC), modified radical mastectomy (MRM), and radiation. We hypothesized that younger patients more frequently receive GCT, resulting in survival differences. METHODS: Using the National Cancer Database (2004-2018), female patients with unilateral IBC (by histology code and clinical stage T4d) were stratified by age (< 50, 50-65, > 65 years). Factors associated with NAC, MRM, radiation, and "GCT" (defined as all three treatments) were identified using multivariable logistic regression. Multivariable Cox proportional hazards regression identified predictors of overall survival. RESULTS: Of 3278 IBC patients, 30% were younger than 50 years, 44% were 50-65 years of age, and 26% were older than 65 years. The youngest group comprised the greatest proportion of non-White patients ([35%] vs. [29%] age 50-65 years and [23%] age > 65 years, p < 0.001) and was most often treated at academic facilities ([33%] vs. [28%] age 50-65 years; and [23%] age > 65, p < 0.001). Patients older than 65 years received NAC, MRM, and radiation less frequently, and only 35% underwent GCT (vs. [57%] age 50-65 years and [52%] age < 50 years; p < 0.001). On multivariable logistic regression, age older than 65 years independently predicted omission of NAC (odds ratio [OR], 0.36), MRM (OR, 0.56), and radiation (OR, 0.56) (all p < 0.001), and patients older than 65 years also were less likely to undergo GCT than patients 50-65 years of age (OR, 0.65; p = 0.001). GCT was associated with superior overall survival in all three age groups ([hazard ratio {HR}, 0.61] age < 50 years, [HR, 0.62] age 50-65 years, [HR, 0.53] age > 65 years; all p < 0.001). CONCLUSION: Advanced age alone should not limit receipt of GCT for IBC. Multimodal care should be performed for IBC patients of all ages to improve oncologic outcomes for this aggressive breast cancer subtype.