CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study.

BACKGROUND: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. METHODS: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. FINDINGS: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. INTERPRETATION: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. FUNDING: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

Highlight of 2023: Advances in mast cells.

In this article for the Highlights of 2023 Series, we consider the growing understanding of mast cell heterogeneity and interactions that has developed from single cell RNA sequencing studies. We also discuss novel concepts concerning mast cell interactions with the central nervous system and evidence for their role in host defense against SARS-CoV-2 infection.

Multicenter, Prospective Trial of Nonendoscopic Biomarker-Driven Detection of Barrett's Esophagus and Esophageal Adenocarcinoma.

INTRODUCTION: Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS: Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS: A total of 243 evaluable patients-88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)-underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78-0.93) and specificity was 85% (95% confidence interval 0.79-0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION: EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Comparative transcriptome analysis of acne vulgaris, rosacea, and hidradenitis suppurativa supports high-dose dietary zinc as a therapeutic agent.

Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc-binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high-dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model.

A dyadic analysis of financial toxicity and health-related quality of life among bone marrow transplant patients and their caregivers.

OBJECTIVE: Relatively few dyad-based studies have evaluated the shared psychosocial and financial toxicity (FT) experiences of hematologic patients and their caregivers, especially those undergoing bone marrow transplantations (BMTs). This study evaluated the association of FT with health-related quality of life (QOL) among BMT patient-caregiver dyads. METHODS: Survey and electronic health record data were collected between April 2021 and January 2022 from BMT patients and their caregivers pre- (T1) and post-intervention (T2). Thirty-four patient-caregiver dyads completed surveys; all dyads included a patient experiencing elevated T1 FT. The effect of the total FT score (i.e., the combination of psychological response, coping behaviors, and material conditions domain scores) on physical health, mental health, anxiety, depression and distress scores was evaluated using Actor-Partner Interdependence Modeling (APIM). RESULTS: Patients and caregivers who reported lower total FT scores had better physical and mental health, and lower anxiety, depressive symptoms, distress (APIM actor effects). None of the partner effects were significant in the APIM models. Other model findings indicated that compared with caregivers, patients had lower reported physical health; mental health scores were higher, on average, for all participants at the T2 compared with T1; and members of dyads whose caregiver took time off work reported better physical health and lower depressive symptoms and distress than those whose caregiver did not. CONCLUSIONS: Our study addresses a significant gap in dyad-based cancer FT studies; the findings underscore the need for additional research to help develop tailored dyad-level FT interventions for improving health-related QOL among BMT patients.

An In Vivo Model of Human Macrophages in Metastatic Melanoma.

Despite recent therapeutic progress, advanced melanoma remains lethal for many patients. The composition of the immune tumor microenvironment (TME) has decisive impacts on therapy response and disease outcome, and high-dimensional analyses of patient samples reveal the heterogeneity of the immune TME. Macrophages infiltrate TMEs and generally associate with tumor progression, but the underlying mechanisms are incompletely understood. Because experimental systems are needed to elucidate the functional properties of these cells, we developed a humanized mouse model reconstituted with human immune cells and human melanoma. We used two strains of recipient mice, supporting or not supporting the development of human myeloid cells. We found that human myeloid cells favored metastatic spread of the primary tumor, thereby recapitulating the cancer-supportive role of macrophages. We next analyzed the transcriptome of human immune cells infiltrating tumors versus other tissues. This analysis identified a cluster of myeloid cells present in the TME, but not in other tissues, which do not correspond to canonical M2 cells. The transcriptome of these cells is characterized by high expression of glycolytic enzymes and multiple chemokines and by low expression of gene sets associated with inflammation and adaptive immunity. Compared with humanized mouse results, we found transcriptionally similar myeloid cells in patient-derived samples of melanoma and other cancer types. The humanized mouse model described here thus complements patient sample analyses, enabling further elucidation of fundamental principles in melanoma biology beyond M1/M2 macrophage polarization. The model can also support the development and evaluation of candidate antitumor therapies.

Does a novel community-based outpatient palliative care intervention for Parkinson's disease and related disorders improve care? Qualitative results from patients and care partners.

BACKGROUND: Palliative care has the potential to address significant unmet needs in people with Parkinson's disease and related disorders, but models that rely on in-person specialty palliative care teams have limited scalability. AIM: To describe patient and care partner experiences with a novel, community-based palliative care intervention for Parkinson's disease. DESIGN: Qualitative study embedded in a randomized clinical trial to document participant experiences with a novel palliative care intervention (community neurologist training and remote team-based specialist palliative care). Transcripts were coded and thematically analyzed through a combination of team-based inductive and deductive coding. SETTING/PARTICIPANTS: Twenty-eight patients and 33 care partners purposively sampled from participants in a randomized clinical trial of a palliative care intervention for Parkinson's disease and related disorders conducted at nine sites. RESULTS: Benefits of the intervention included management of a wider range of non-motor symptoms, facilitation of conversations about the future, greater engagement with the health care team, and increased referrals to resources. Participants identified areas of improvement, including uptake of palliative care training by community neurologists, additional prognostic counseling, and clarity and timeliness of communication with the multidisciplinary team. CONCLUSIONS: Clinicians caring for people with Parkinson's disease and related disorders should screen for non-motor symptoms, provide regular prognostic counseling, and refer to specialty palliative care services earlier in the course of illness. Future interventions should be designed to promote uptake of palliative care training by community neurologists and further optimize referral to and coordination with in-person or remote specialty palliative teams.

Patients With Esophageal Adenocarcinoma With Prior Gastroesophageal Reflux Disease Symptoms Are Similar to Those Without Gastroesophageal Reflux Disease: A Cross-Sectional Study.

INTRODUCTION: A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. METHODS: In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. RESULTS: Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC-related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. DISCUSSION: Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

Novel inflammatory mediator profile observed during pediatric heart surgery with cardiopulmonary bypass and continuous ultrafiltration.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators. METHODS: Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated. RESULTS: A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi2 statistic = 18.8, Chi2 with Yates' correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = - 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF. CONCLUSIONS: CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery. Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864 .

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

BACKGROUND: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways. OBJECTIVES: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO. METHODS: This phase IIb multicentre randomized double-blind study was conducted in two stages. In stage 1, participants received one of eight treatments for 12 weeks: brepocitinib 0.1% once daily, 0.3% once or twice daily, 1.0% once or twice daily, 3.0% once daily, or vehicle once or twice daily. In stage 2, participants received brepocitinib 3.0% twice daily or vehicle twice daily. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment response [score of clear (0) or almost clear (1) and an improvement of ≥ 2 points from baseline] at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures, and the change from baseline in Peak Pruritus Numerical Rating Scale at week 12. Safety was monitored. RESULTS: Overall, 344 participants were randomized. Topical brepocitinib did not result in statistically significant changes compared with respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean change from baseline in PASI score ranged from -1.4 to -2.4 for the brepocitinib once-daily groups vs. -1.6 for vehicle once daily, and from -2.5 to -3.0 for the brepocitinib twice-daily groups vs. -2.2 for vehicle twice daily. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib twice daily groups. Brepocitinib was well tolerated, with adverse events (AEs) occurring at similar rates across groups. One participant in the brepocitinib 1.0% once-daily group developed a treatment-related AE of herpes zoster in the neck area. CONCLUSIONS: Topical brepocitinib was well tolerated but did not result in statistically significant changes compared with vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO.

Best Practice Alerts Informed by Inpatient Opioid Intake to Reduce Opioid Prescribing after Surgery (PRIOR): A Cluster Randomized Multiple Crossover Trial.

BACKGROUND: Overprescription of opioids after surgery remains common. Residual and unnecessarily prescribed opioids can provide a reservoir for nonmedical use. This study therefore tested the hypothesis that a decision-support tool embedded in electronic health records guides clinicians to prescribe fewer opioids at discharge after inpatient surgery. METHODS: This study included 21,689 surgical inpatient discharges in a cluster randomized multiple crossover trial from July 2020 to June 2021 in four Colorado hospitals. Hospital-level clusters were randomized to alternating 8-week periods during which an electronic decision-support tool recommended tailored discharge opioid prescriptions based on previous inpatient opioid intake. During active alert periods, the alert was displayed to clinicians when the proposed opioid prescription exceeded recommended amounts. No alerts were displayed during inactive periods. Carryover effects were mitigated by including 4-week washout periods. The primary outcome was oral morphine milligram equivalents prescribed at discharge. Secondary outcomes included combination opioid and nonopioid prescriptions and additional opioid prescriptions until day 28 after discharge. A vigorous state-wide opioid education and awareness campaign was in place during the trial. RESULTS: The total postdischarge opioid prescription was a median [quartile 1, quartile 3] of 75 [0, 225] oral morphine milligram equivalents among 11,003 patients discharged when the alerts were active and 100 [0, 225] morphine milligram equivalents in 10,686 patients when the alerts were inactive, with an estimated ratio of geometric means of 0.95 (95% CI, 0.80 to 1.13; P = 0.586). The alert was displayed in 28% (3,074 of 11,003) of the discharges during the active alert period. There was no relationship between the alert and prescribed opioid and nonopioid combination medications or additional opioid prescriptions written after discharge. CONCLUSIONS: A decision-support tool incorporated into electronic medical records did not reduce discharge opioid prescribing for postoperative patients in the context of vigorous opioid education and awareness efforts. Opioid prescribing alerts might yet be valuable in other contexts.(Anesthesiology 2023; 139:186-96).

Patient Factors Affect Ergonomic Strain of Endoscopists During Colonoscopy.

INTRODUCTION: Endoscopic procedures place a great deal of muscular strain on providers, especially over the span of their careers. In this study we quantitatively analyzed the effects of patient factors such as age, body mass index, and sex on the ergonomics of endoscopists performing colonoscopies. METHODS: Surface electromyography (sEMG) was used to measure ergonomic strain of physicians while performing colonoscopies in several key muscle groups. The percent of the maximum voluntary contraction (%MVC) was used as a measure of muscular strain. Data was then analyzed based on the patient characteristics above. RESULTS: Endoscopists performing colonoscopies on female patients (n = 47) experienced significantly higher ergonomic strain in their right trapezius and right posterior forearm muscle groups when compared to colonoscopies performed on males (n = 35) (%MVC R-trapezius: Male: 8.2; Female: 8.9; p = 0.048); (%MVC R-posterior forearm: Male: 10.4; Female: 11.6; p = 0.0006). Operators experienced greater strain in the same muscle groups when performing colonoscopies on patients with BMI ≤ 25 (n = 25) when compared to patients with BMI > 25 (n = 57) (%MVC R-trapezius: BMI < 25: 9.7; BMI ≥ 25: 8.2; p = 0.0002); (%MVC R-posterior forearm: BMI < 25: 11.9; BMI ≥ 25: 10.8; p = 0.0001). CONCLUSION: Physicians experienced greater ergonomic strain when performing colonoscopies on female patients and on patients with a BMI < 25. We believe that these factors potentially impact the tortuosity of the colon and therefore influence the difficulty of navigating the endoscope. These results may aid physicians in gauging the anticipated difficulty of colonoscopies based on patient factors. Increased awareness of their posturing and ergonomics during challenging cases will alleviate musculoskeletal injuries in the long run.

Effect of reverse Trendelenburg position and positive pressure ventilation on safe non-hypoxic apnea period in obese, a randomized-control trial.

PURPOSE: There is an elevated incidence of hypoxemia during the airway management of the morbidly obese. We aimed to assess whether optimizing body position and ventilation during pre-oxygenation allow a longer safe non-hypoxic apnea period (SNHAP). METHODS: Fifty morbidly obese patients were recruited and randomized for this study. Patients were positioned and preoxygenated for three minutes in the ramp position associated with spontaneous breathing without additional CPAP or PEEP (RP/ZEEP group) or in the reverse Trendelenburg position associated with pressure support ventilation mode with pressure support of 8 cmH2O and an additional 10 cmH2O of PEEP while breathing spontaneously (RT/PPV group) according to randomization. RESULTS: The SNHAP was significantly longer in the RT/PPV group (258.2 (55.1) vs. 216.7 (42.3) seconds, p = 0.005). The RT/PPV group was also associated to a shorter time to obtain a fractional end-tidal oxygen concentration (FEtO2) of 0.90 (85.1(47.8) vs 145.3(40.8) seconds, p < 0.0001), a higher proportion of patients that reached the satisfactory FEtO2 of 0.90 (21/24, 88% vs. 13/24, 54%, p = 0.024), a higher FEtO2 during preoxygenation (0.91(0.05) vs. 0.89(0.01), p = 0.003) and a faster return to 97% oxygen saturation after ventilation resumption (69.8 (24.2) vs. 91.4 (39.2) seconds, p = 0.038). CONCLUSION: In the morbidly obese population, RT/PPV, compared to RP/ZEEP, lengthens the SNHAP, decreases the time to obtain optimal preoxygenation conditions, and allows a faster resuming of secure oxygen saturation. The former combination allows a more significant margin of time for endotracheal intubation and minimizes the risk of hypoxemia in this highly vulnerable population. TRIAL REGISTRATION: NCT02590406, 29/10/2015.

Dissemination and Implementation of a Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC): a study protocol for a hybrid type 1 randomized controlled trial.

BACKGROUND: There are persistent racial and ethnic health disparities in end-of-life health outcomes in the United States. African American patients are less likely than White patients to access palliative care, enroll in hospice care, have documented goals of care discussions with their healthcare providers, receive adequate symptom control, or die at home. We developed Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC) to address these disparities. DeCIDE PC is an integrated community health worker (CHW) palliative care intervention that uses community health workers (CHWs) as care team members to enhance the receipt of palliative care for African Americans with advanced cancer. The overall objectives of this study are to (1) assess the effectiveness of the DeCIDE PC intervention in improving palliative care outcomes amongst African American patients with advanced solid organ malignancy and their informal caregivers, and (2) develop generalizable knowledge on how contextual factors influence implementation to facilitate dissemination, uptake, and sustainability of the intervention. METHODS: We will conduct a multicenter, randomized, assessor-blind, parallel-group, pragmatic, hybrid type 1 effectiveness-implementation trial at three cancer centers across the United States. The DeCIDE PC intervention will be delivered over 6 months with CHW support tailored to the individual needs of the patient and caregiver. The primary outcome will be advance care planning. The treatment effect will be modeled using logistic regression. The secondary outcomes are quality of life, quality of communication, hospice care utilization, and patient symptoms. DISCUSSION: We expect the DeCIDE PC intervention to improve integration of palliative care, reduce multilevel barriers to care, enhance clinic and patient linkage to resources, and ultimately improve palliative care outcomes for African American patients with advanced cancer. If found to be effective, the DeCIDE PC intervention may be a transformative model with the potential to guide large-scale adoption of promising strategies to improve palliative care use and decrease disparities in end-of-life care for African American patients with advanced cancer in the United States. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT05407844). First posted on June 7, 2022.

Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus.

BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.

Multi-variable compensated quantum yield measurements of upconverting nanoparticles with high dynamic range: a systematic approach.

Non-linear materials such as upconverting nanoparticles (UCNPs) are emerging technology with fast-growing applications in various fields. The power density dependence of the emission quantum yield (QY) of these non-linear materials makes them challenging to characterize using currently available commercial QY systems. We propose a multimodal system to measure QY over a wide dynamic range (1:104), which takes into account and compensates for various distorting parameters (scattering, beam profile, inner filter effect and bandwidth of emission lines). For this, a beam shaping approach enabling speckle free beam profiles of two different sizes (530 µm or 106 µm) was employed. This provides low noise high-resolution QY curves. In particular, at low power densities, a signal-to-noise ratio of >50 was found. A Tm-based core-shell UCNP with excitation at 976 nm and emission at 804 nm was investigated with the system.

Yin and Yang of skin microbiota in "swimmer acne".

Cutibacterium acnes (C. acnes) is an organism implicated in the pathogenesis of acne. Despite regular immersion in antimicrobial chlorine, adolescent swimmers suffer from acne and tend to be resistant to standard therapies. Given the presence of Pseudomonas within swimming facilities, we hypothesized that "swimmer acne" is potentially driven by a different microbial mechanism. In this study, we aimed to examine the microbial dynamics of C. acnes and Pseudomonadaceae, a family of gram-negative bacteria (includes Pseudomonas aeruginosa), in swimmers and its potential contribution to the pathogenesis of acne in this population. Using fluorescence photography that measures the Coproporphyrin III (CPIII), we quantitated an absolute abundance of C. acnes present on the face of each participant pre- and post-swimming. In addition, 16S rRNA gene sequencing was utilized to assess relative abundance of the skin microbiota on each participant pre- and post-swimming. 16 swimmers (8 girls and 8 boys) completed the study. Seven had acne on the face. The CPIII fluorescence levels decreased for all swimmers after 1 h of swimming (p-value <0.001). In contrast, the relative abundance of C. acnes remained unchanged, while that of Pseudomonadaceae increased after swimming (p-value =0.027). Comparing the relative abundances of Pseudomonadaceae before swimming, there was a significant increase in variance from the mean in acne group as compared to no acne group (p-value <0.001). Taken together, we conclude that the skin dysbiosis resulting from repeated decolonization and colonization of C. acnes and Pseudomonadaceae, respectively, can potentially be associated with the pathogenesis of acne in swimmers.

Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study.

BACKGROUND: Atopic dermatitis (AD) is a prevalent inflammatory, pruritic skin disease. The Janus kinase (JAK) pathway is a treatment target. OBJECTIVES: To assess the efficacy, safety and pharmacokinetics of topical cream brepocitinib, a small-molecule tyrosine kinase 2 (TYK2)/JAK1 inhibitor, in participants with mild-to-moderate AD. METHODS: In this phase IIb, double-blind, dose-ranging study, participants were randomized to receive one of eight treatments for 6 weeks: brepocitinib 0·1% once daily (QD), 0·3% QD or twice daily (BID), 1·0% QD or BID, 3·0% QD, or vehicle QD or BID. The primary endpoint was the percentage change from baseline in the Eczema Area and Severity Index (EASI) total score at week 6. Adverse events (AEs) were monitored. RESULTS: Overall, 292 participants were enrolled and randomized. The brepocitinib 1% QD and 1% BID groups achieved statistically significantly greater (with multiplicity-adjusted P < 0·05 due to Hochberg's step-up method) percentage reductions from baseline in EASI total score at week 6 [least squares mean (90% confidence interval, CI): QD: -70·1 (-82·1 to -58·0); BID: -75·0 (-83·8 to -66·2)] compared with respective vehicle [QD: -44·4 (-57·3 to -31·6); BID: -47·6 (-57·5 to -37·7)]. There was not a dose-dependent trend in AE frequency, and there were no serious AEs or deaths. CONCLUSIONS: Topical brepocitinib is effective and well tolerated in participants with mild-to-moderate AD. What is already known about this topic? Janus kinase (JAK) inhibitors are in development for treatment of atopic dermatitis (AD). The tyrosine kinase 2 and JAK 1 inhibition by brepocitinib may bring a new profile for topical JAK inhibitors for treatment of mild-to-moderate AD. What does this study add? Topical brepocitinib can provide rapid, effective symptom reduction, and could offer a novel alternative to current topical treatments for mild-to-moderate AD.

Smaller hands and less experience are associated with greater ergonomic strain during endoscopic procedures.

INTRODUCTION: Up to 89% of physicians who routinely perform endoscopy experience some type of musculoskeletal pain. In this study, we sought to quantitatively analyze provider factors that influence ergonomic strain during live endoscopic procedures. METHODS: Surface electromyography (sEMG) was used to measure ergonomic strain on physicians while performing upper and lower endoscopies. EMG data were normalized to a maximal voluntary contraction (MVC) recording for each muscle group, yielding a %MVC value. Subgroup analyses were performed based on glove size, physician training level, specialty, and handedness. RESULTS: A total of 165 upper (n = 68) and lower (n = 97) endoscopies were recorded. Endoscopists with small hand sizes had significantly higher ergonomic strain in the left anterior and posterior forearm muscle compartments as compared to endoscopists with medium or large hands (%MVC L-anterior: small: 9.1 ± 1.1; medium: 6.4 ± 1.2; large: 5.9 ± 1.6; p < 0.001); (%MVC L-posterior: small: 12.0 ± 0.8; medium: 9.4 ± 1.3; large: 8.8 ± 1.4; p < 0.001). Additionally, upper body muscle groups had significantly higher ergonomic strain in endoscopists with less lifetime endoscopic experience (%MVC R-trapezius: expert: 8.4 ± 1.2; novice: 9.3 ± 1.2; p < 0.05); (%MVC R-deltoid: expert: 6.1 ± 1.4; novice: 8.5 ± 1.3; p < 0.001). There were no significant ergonomic differences between surgeons or gastroenterologists and no differences between right- and left-handed dominant individuals. CONCLUSIONS: Endoscopists with small hands experienced great ergonomic strain in their left forearm. Our data support the widely held belief that "one size does not fit all" and will hopefully spark change in the design of future endoscopes by device manufacturers. Our data also support that the experience level of the endoscopist contributed significantly to ergonomic performance, likely due to postural differences leading to decreased upper body strain. Therefore, it remains critically important to educate young proceduralists on strategies for ergonomic relief early in his or her endoscopic training program that can ameliorate ergonomic strain that accrues over the lifetime of a physician's career.