The Anomalous Effect of COVID-19 Pandemic Restrictions on the Duration of Untreated Psychosis (DUP).

We investigated the impact of COVID-19 restrictions on the duration of untreated psychosis (DUP). First-episode psychosis admissions (n=101) to STEP Clinic in Connecticut showed DUP reduction (p=.0015) in the pandemic, with the median reducing from 208 days during the pre-pandemic to 56 days in the early pandemic period and subsequently increasing to 154 days (p=.0281). Time from psychosis onset to anti-psychotic prescription decreased significantly in the pandemic (p=.0183), with the median falling from 117 to 35 days. This cohort study demonstrates an association between greater pandemic restrictions and marked DUP reduction and provides insights for future early detection efforts.

Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children.

Standard diagnostics used in longitudinal antimalarial studies are unable to characterize the complexity of submicroscopic parasite dynamics, particularly in high transmission settings. We use molecular markers and amplicon sequencing to characterize post-treatment stage-specific malaria parasite dynamics during a 42 day randomized trial of 3- versus 5 day artemether-lumefantrine in 303 children with and without HIV (ClinicalTrials.gov number NCT03453840). The prevalence of parasite-derived 18S rRNA is >70% in children throughout follow-up, and the ring-stage marker SBP1 is detectable in over 15% of children on day 14 despite effective treatment. We find that the extended regimen significantly lowers the risk of recurrent ring-stage parasitemia compared to the standard 3 day regimen, and that higher day 7 lumefantrine concentrations decrease the probability of ring-stage parasites in the early post-treatment period. Longitudinal amplicon sequencing reveals remarkably dynamic patterns of multiclonal infections that include new and persistent clones in both the early post-treatment and later time periods. Our data indicate that post-treatment parasite dynamics are highly complex despite efficacious therapy, findings that will inform strategies to optimize regimens in the face of emerging partial artemisinin resistance in Africa.

Trends and predictors of Quality of Life in lung cancer survivors.

INTRODUCTION: Health-related quality of life (HR-QoL) is often impaired in lung cancer survivors. To inform personalized survivorship care, we identified associations between HR-QoL scores and patient-, tumor-, and treatment-factors over time. MATERIALS AND METHODS: We evaluated HR-QoL scores provided at diagnosis, 6 months, 1 year, and 2 years from the Yale Lung Cancer Biorepository. HR-QoL was measured via the Functional Assessment of Cancer Therapy - Lung (FACT-L) instrument and available for a subset of patients (n = 513). Analyses were stratified by early-stage (I-II; n = 355) non-small cell lung cancer (NSCLC), advanced stage NSCLC (III-IV; n = 158), and small cell lung cancer (SCLC, n = 21). We used mixed effects modeling and multivariable analysis with covariate adjustment to examine changes in FACT-L from diagnosis to follow-up. Sensitivity analysis was performed including patients with early-stage disease and complete FACT-L scores at both baseline and year 2 (n = 91). RESULTS: The average FACT-L scores at diagnosis in early-stage NSCLC, advanced stage NSCLC, and SCLC were 121.0 (standard deviation (SD) 11.4), 109.2 (18.7), and 98.7 (20.2) respectively. At all timepoints, HR-QoL was higher in patients with early-stage NSCLC (vs advanced-stage disease). In patients with early- and advanced-stage NSCLC, HR-QoL was higher at years 1 and 2 than at diagnosis, though the changes did not meet clinical significance. At NSCLC diagnosis, higher HR-QoL was associated with older age, better performance status, participating in physical activity, adenocarcinoma histology, and (in advanced stage NSCLC) anticipated treatment with chemotherapy. At NSCLC follow-up, HR-QoL was higher in patients with higher BMI and better performance status. DISCUSSION: In patients with newly diagnosed NSCLC, HR-QoL scores are impacted by patient factors, tumor factors, and treatment factors. HR-QoL is higher in patients with early-stage disease. In patients surviving 2 years, HR-QoL was higher at follow-up, though the change did not meet clinical significance. To optimize HR-QoL, lung cancer survivorship teams should prioritize comorbidity management, physical activity, healthy weight maintenance, and treatment-related side effects.

Improving lifestyle behaviors during chemotherapy for breast cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis (LEANer) Trial.

BACKGROUND: Little is known about improving physical activity (PA) and diet during and after chemotherapy for breast cancer. This secondary analysis examines changes in PA and diet quality during a yearlong intervention for patients with breast cancer undergoing chemotherapy and evaluates factors associated with these changes. METHODS: Newly diagnosed patients with breast cancer (N = 173) undergoing chemotherapy were randomized to a year-long nutrition and exercise intervention (n = 87) or usual care (UC, n = 86). Mixed models compared 1-year changes in PA and diet quality via the Healthy Eating Index (HEI)-2015 by study arm. Among the intervention group, baseline factors associated with change in PA and diet were assessed with multivariable linear and logistic regression. RESULTS: At 1 year, compared with UC, the intervention arm increased PA more (mean difference = 136.1 minutes/week; 95% CI, 90.2-182.0), participated in more strength training (56% vs. 15%; p < .001), and had suggestive improvements in HEI-2015 (mean difference = 2.5; 95% CI, -0.3 to 5.3; p = .08). In the intervention arm, lower fatigue was associated with improved PA (p = .04) and higher education was associated with improved HEI-2015 (p = .001) at 1 year. Higher HEI-2015 (p = .04) and married/living with someone (p = .05) were associated with higher odds of participating in strength training at 1 year. CONCLUSIONS: This year-long lifestyle intervention for patients with breast cancer undergoing chemotherapy resulted in increases in PA and suggestive improvements in diet quality. Behavior change was associated with baseline fatigue, diet quality, education, and married/living with someone. Addressing these factors in interventions may improve uptake of lifestyle behaviors in trials during and after chemotherapy.

The impact of early detection (ED) campaigns on care presentations: Beyond DUP reduction.

We examined the effects of an early detection (ED) campaign (Mindmap), that successfully shortened the duration of untreated psychosis (DUP), on patient presentation profiles at two receiving coordinated specialty care (CSC) services. Data were collected between 2015 and 2019 during a test of ED delivered at one CSC (STEP, n = 147) compared to usual detection at another CSC (PREP, n = 63). Regression models were used to test the effects of ED and DUP on presentation. Before the launch of ED, there were no differences in presentation between STEP and PREP. However, the ED changed the profile of presentations to STEP such that patients were admitted with better negative and total symptoms scores, but worse GAF current and GAF social and with a greater decline in function over the prior year (GAF-Δ). Site-by-time interaction effects were not significant. During the campaign years, STEP vs. PREP recruited patients with better negative and total symptoms, GAF role, and pre-morbid adjustment scores but with worse positive symptoms, GAF current, and GAF-Δ. Nonetheless, mediation analysis revealed that DUP reduction accounted for very little (<8 %) of these differences in presentation. Early detection campaigns while successfully reducing access delays, can have salutary effects on presentation independent of DUP reduction.

Role of Early Psychosis Detection in the Relationship Between Personal Income and Duration of Untreated Psychosis.

OBJECTIVE: Prolonged duration of untreated psychosis (DUP) predicts poor outcomes of first-episode psychosis (FEP) and is often linked to low socioeconomic status (SES). The authors sought to determine whether patients' personal income, used as a proxy for SES, predicts length of DUP and whether personal income influences the effect of an early psychosis detection campaign-called Mindmap-on DUP reduction. METHODS: Data were drawn from a trial that compared the effectiveness of early detection in reducing DUP across the catchment area of an FEP service (N=147 participants) compared with an FEP service with no early detection (N=75 participants). Hierarchical regression was used to determine whether personal income predicted DUP when analyses controlled for effects of age, race, and exposure to early psychosis detection. A group × personal income interaction term was used to assess whether the DUP difference between the early detection and control groups differed by personal income. RESULTS: Lower personal income was significantly associated with younger age, fewer years of education, Black race, and longer DUP. Personal income predicted DUP beyond the effects of age, race, and early psychosis detection. Although Mindmap significantly reduced DUP across all income levels, this effect was smaller for participants reporting lower personal income. CONCLUSIONS: Patients' personal income may be an important indicator of disparity in access to specialty care clinics across a wide range of settings. Early detection efforts should measure and target personal income and other SES indicators to improve access for all individuals who may benefit from FEP services.

Effect of a Personalized Tobacco Treatment Intervention on Smoking Abstinence in Individuals Eligible for Lung Cancer Screening.

INTRODUCTION: To determine whether personalized gain-framed messaging and biomarker feedback related to tobacco cessation or reduction decrease smoking behavior in patients undergoing or eligible for lung cancer screening. METHODS: Between 2016 and 2020, 188 patients were enrolled in a two-phase, sequential, randomized controlled trial. Phase 1 evaluated whether standard of care (SC) (five in-person counseling sessions and 8 weeks of nicotine patch) plus gain-framed messaging (GFM) versus SC would increase 8-week biochemically verified smoking cessation rates. In 143 participants randomized in phase 2, we tested whether feedback on smoking-related biomarkers would reduce 6-month self-reported number of cigarettes smoked per day compared with a no feedback control. Chi-square test and mixed effects repeated measures analyses were used to evaluate group differences. RESULTS: Participants were 62.5 ± 5.6 (mean ± SD) years of age, had a 50.3 ± 21 pack-year smoking history, and were smoking 16.9 ± 9.9 cigarettes per day. At 8 weeks, there was no difference in quit rates between those randomized to SC plus GFM (n = 15 of 93, 16.1%) and those randomized to SC (n = 16 of 95, 16.8%), with p equals to 0.90. At the 6-month post-randomization follow-up, number of cigarettes smoked per day was similar in the feedback (least-squares mean = 7.5, 95% confidence interval: 6.0-9.1) and no feedback arms (7.7, 95% confidence interval: 6.2-9.3), with p equals to 0.87. CONCLUSIONS: Gain-framed messaging and health feedback did not significantly improve quit rates relative to comprehensive standard of care. Nevertheless, the overall program achieved clinically meaningful smoking quit rates in this older high pack-year cohort, highlighting the importance of intensive tobacco treatment for patients undergoing lung cancer screening. CLINICAL TRIAL REGISTERED WITH CLINICALTRIALS.GOV: NCT02658032.

Agreement and Reliability of Patient-measured Postvoid Residual Bladder Volumes.

OBJECTIVE: To assess the reliability, agreement with provider measurement, and patient preferences regarding patient self-measurement of postvoid residual bladder volume (PVR). PVR measurement in the nonhealthcare setting is a valuable opportunity for remote monitoring of voiding dysfunction patients. We hypothesized that patient self-measurement of PVR using a smart-device portable ultrasound system with artificial intelligence would demonstrate high reliability, strong agreement with provider measurement, and be preferred over provider measurements. METHODS: Patients were enrolled during outpatient Urology visits. PVRs were measured in triplicate by providers using each of the following: an FDA-cleared (standard) bladder scanner, the portable ultrasound probe using ultrasound images (Butterfly US image mode), and the portable ultrasound probe using abstract images (Butterfly abstract mode). Subjects self-measured PVRs in triplicate using both imaging modes and reported their experiences via questionnaire. Reliability was assessed via intraclass correlation. Agreement between methods was assessed via Bland-Altman analyses using a clinically acceptable difference threshold of 50 mL. RESULTS: Fifty patients were enrolled. Intraclass correlations ranged from 0.95 to 0.98 for each method. 95% limits of agreement between standard bladder scanner and patient self-measurement were - 71.73 mL and 86.73 mL using Butterfly US image mode and - 93.84 mL and 112.52 mL using Butterfly abstract mode, respectively. Most patients preferred self-measurement over provider measurement (74% vs 26%, respectively). CONCLUSION: Patient self-measurement of PVR using smart-device integrated portable ultrasound probes is feasible, reliable, and preferred by patients. Limits of agreement between patient self-measurement and standard bladder scanner measurements exceeded our clinically acceptable difference threshold, though the inherent error of ultrasound-based bladder volume measurements should be considered. Longitudinal PVR assessments in nonhealthcare settings may facilitate remote monitoring of voiding dysfunction patients.

Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer.

INTRODUCTION: Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited. METHODS: Patients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53mut/TSGmut), those having a TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and those with TP53wt. Patient characteristics and clinical outcomes were assessed in two independent cohorts. RESULTS: A total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53mut/TSGmut and 42 were TP53mut/TSGwt. Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53mut tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53mut/TSGmut tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53mut/TSGwt (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12-3.69, p < 0.01, OS: HR = 1.58, CI: 0.82-3.04, p = 0.12) or TP53wt cases (PFS: HR 2.4, CI: 1.28-4.47, p < 0.001, OS: HR = 2.54, CI: 1.21-5.34, p < 0.005). Inferior outcomes in patients with TP53mut/TSGmut tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort. CONCLUSIONS: Patients with TP53mut/TSGmut tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy.

Post-diagnosis weight trajectories and mortality among women with breast cancer.

Weight gain after breast cancer diagnosis is associated with adverse health outcomes. Yet, few studies have characterized post-diagnosis weight change in the modern treatment era or populations most at risk for weight changes. Among women diagnosed with stages I-III breast cancer in the Smilow Care Network (2013-2019; N = 5441), we abstracted demographic and clinical characteristics from electronic health records and survival data from tumor registries. We assessed if baseline characteristics modified weight trajectories with nonlinear multilevel mixed-effect models. We evaluated body mass index (BMI) at diagnosis and weight change 1-year post-diagnosis in relation to all-cause and breast cancer-specific mortality with Cox proportional hazard models. Women had 34.4 ± 25.5 weight measurements over 3.2 ± 1.8 years of follow-up. Weight gain was associated with ER/PR-, HER2+ tumors, BMI ≤ 18.5 kg/m2, and age ≤ 45 years (+4.90 kg (standard error [SE] = 0.59), +3.24 kg (SE = 0.34), and +1.75 kg (SE = 0.10), respectively). Weight loss was associated with BMI ≥ 35 kg/m2 and age ≥ 70 years (-4.50 kg (SE = 0.08) and -4.34 kg (SE = 0.08), respectively). Large weight loss (≥10%), moderate weight loss (5-10%), and moderate weight gain (5-10%) 1-year after diagnosis were associated with higher all-cause mortality (hazard ratio [HR] = 2.93, 95% confidence interval [CI] = 2.28-3.75, HR = 1.32, 95% CI = 1.02-1.70 and HR = 1.39, 95% CI = 1.04-1.85, respectively). BMI ≥ 35 kg/m2 or BMI ≤ 18.5 kg/m2 at diagnosis were also associated with higher all-cause mortality. Weight change after a breast cancer diagnosis differed by demographic and clinical characteristics highlighting subgroups at-risk for weight change during a 5-year period post-diagnosis. Monitoring and interventions for weight management early in clinical care are important.

Perioperative Complications in Patients with Systemic Sclerosis: A Comparative Cohort Analysis.

Background: Systemic sclerosis (SSc) is a rare autoimmune disorder with pathological manifestations affecting multiple organ systems. Few studies have examined perioperative outcomes in patients with this disorder. The primary aim of this retrospective single-center comparative cohort analysis was to estimate the incidence of select perioperative complications in a population of SSc patients. In an exploratory analysis, we analyzed the relationship between SSc and susceptibility to select perioperative complications when treated at a large quaternary-care institution. Methods: We conducted a single-center retrospective, comparative cohort study to compare perioperative outcomes in a SSc (n=258) and a frequency matched control cohort (n=632). We analyzed for the presence of major composite infection (MCI), major adverse cardiac events (MACE), 30-day readmission, 30-day mortality, in-hospital complications, length of stay and airway management outcomes. Results: MCI was higher in the SSc compared to the control cohort [adjusted odds ratio (ORadj)=5.02 (95%CI: 2.47-10.20) p<0.001]. Surgical site infection (3.5% vs. 0%, p<0.001), and other infection types (5% vs. 0%, p<0.001) were higher in the SSc cohort. MACE was not significantly different between SSc vs. Control groups [6.2% vs. 7.9%, ORadj=1.33 (95%CI: 0.61-2.91) p=0.48]. Higher rates of limited cervical range of motion (13.6% vs. 3.5%, p<0.001), microstomia (11.5% vs. 1.3%, p<0.001) and preoperative difficult airway designation (8.7% vs. 0.5%, p<0.001) were observed in the SSc cohort. Bag mask ventilation grade was similar between groups (p=0.44). After adjustment, there was no between-group difference in Cormack-Lehane grade 3 and 4 view on direct laryngoscopy in SSc patients [ORadj = 1.86 (95%CI: 0.612 -5.66) p=0.18] but evidence of higher rates of video laryngoscopy [ORadj= 1.87 (95%CI:1.07 - 3.27) p=0.03]. Length of stay [median: 0.2 vs. 0.3 days, p=0.08], 30-day mortality [1.2% vs. 0.6%, ORadj=2.79 (95%CI: 0.50-15.6) p=0.24] and readmission [11.5% vs. 8.1%, ORadj=1.64 (95%CI: 0.96 - 2.82) p=0.07] were not statistically significant. Conclusions: SSc patients demonstrate mostly similar rates of MACE, 30-day mortality, length of stay intraoperative and airway complications. There is evidence of increased risk of overall 30-day MCI risk and readmission after endoscopic procedures.

A structured multi-head attention prediction method based on heterogeneous financial data.

The diverse characteristics of heterogeneous data pose challenges in analyzing combined price and volume data. Therefore, appropriately handling heterogeneous financial data is crucial for accurate stock prediction. This article proposes a model that applies customized data processing methods tailored to the characteristics of different types of heterogeneous financial data, enabling finer granularity and improved feature extraction. By utilizing the structured multi-head attention mechanism, the model captures the impact of heterogeneous financial data on stock price trends by extracting data information from technical, financial, and sentiment indicators separately. Experimental results conducted on four representative individual stocks in China's A-share market demonstrate the effectiveness of the proposed method. The model achieves an average MAPE of 1.378%, which is 0.429% lower than the benchmark algorithm. Moreover, the backtesting return rate exhibits an average increase of 28.56%. These results validate that the customized preprocessing method and structured multi-head attention mechanism can enhance prediction accuracy by attending to different types of heterogeneous data individually.

Randomized Trial Evaluating a Self-Guided Lifestyle Intervention Delivered via Evidence-Based Materials versus a Waitlist Group on Changes in Body Weight, Diet Quality, Physical Activity, and Quality of Life among Breast Cancer Survivors.

Background: Lifestyle interventions for breast cancer survivors have proved effective at stimulating positive behavior change and promoting healthy weight loss, although integrating these programs into clinical practice is challenging. We evaluated the effect of a 6-month, unsupervised, self-guided, lifestyle intervention using printed materials and online videos vs. waitlist group on body weight for breast cancer survivors. Methods: The Lifestyle, Exercise and Nutrition (LEAN) Self-Guided trial randomized breast cancer survivors with a body mass index ≥25 kg/m2 to a 6-month lifestyle intervention (N = 102) or waitlist group (N = 103). Effects of the intervention on self-reported body weight, physical activity (PA), diet quality (via Health Eating Index-2010 (HEI-2010)), and quality of life were assessed using mixed model repeated measures analysis. Results: At 6 months, the intervention arm had significantly greater weight loss compared with the waitlist group (mean difference = -1.3 kg, 95% confidence interval [CI] = -2.5, -0.13). We observed suggestive improvements in PA (mean difference = 18.7 min/week, 95% CI = -24.2, 61.6), diet quality (mean difference in HEI = 3.2 points, 95% CI = -0.20, 6.5), and fatigue (mean difference in Functional Assessment of Chronic Illness Therapy-Fatigue scale = 1.4 points, 95% CI = -1.1, 3.9). Conclusions: The LEAN Self-Guided intervention led to favorable weight changes over 6 months. Low-resource-intensive programs have the potential to be delivered in diverse healthcare settings and may support breast cancer survivors in achieving a healthy body weight.

The effect of duration of untreated psychosis (DUP) on the risk for hospitalization after admission to a first episode service.

Engagement with a first episode-psychosis service (FES) reduces the risk of psychiatric hospitalization. However, the role of the duration of untreated psychosis (DUP) in impacting this outcome is disputed. This study aimed to examine whether DUP was an effect modifier of the post-FES reduction of risk of hospitalization, and to explore associations between patients' characteristics and hospitalization post-FES. Individuals aged 16-35 with recent onset (< 3 years) of non-affective psychosis, admitted to the Program for Specialized Treatment Early in Psychosis (STEP), a FES serving the Greater New Haven area, Connecticut, between 2014 and 2019 were included (N = 189). Medical records were queried from 2013 through 2020 for number and duration of psychiatric hospitalizations. Poisson regression models were used to estimate incidence rate ratios for hospitalization rates across all explanatory variables. Negative binomial regression was used to compare the length of stay (LOS) before vs after STEP enrollment. STEP admission was associated with a significant 90 % reduction in the frequency and duration of hospitalizations. This effect was moderated by DUP: with 30-day prolongations in components of DUP (supply, demand, and total) there was less reduction in hospitalizations and LOS after FES enrollment (p < .0001). Only DUP supply (time from first antipsychotic use to STEP admission) differentiated those who were hospitalized during the first year after STEP enrollment from those who were not (median: 35 vs. 15 weeks, p = .003). To fully harness the positive impact of FES on hospitalization, a detailed effort should be pursued to reduce all DUP components.

Randomized Trial of Exercise and Nutrition on Chemotherapy Completion and Pathologic Complete Response in Women With Breast Cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis Study.

PURPOSE: Successful completion of chemotherapy is critical to improve breast cancer outcomes. Relative dose intensity (RDI), defined as the ratio of chemotherapy delivered to prescribed, is a measure of chemotherapy completion and is associated with cancer mortality. The effect of exercise and eating a healthy diet on RDI is unknown. We conducted a randomized trial of an exercise and nutrition intervention on RDI and pathologic complete response (pCR) in women diagnosed with breast cancer initiating chemotherapy. METHODS: One hundred seventy-three women with stage I-III breast cancer were randomly assigned to usual care (UC; n = 86) or a home-based exercise and nutrition intervention with counseling sessions delivered by oncology-certified registered dietitians (n = 87). Chemotherapy dose adjustments and delays and pCR were abstracted from electronic medical records. T-tests and chi-square tests were used to examine the effect of the intervention versus UC on RDI and pCR. RESULTS: Participants randomly assigned to intervention had greater improvements in exercise and diet quality compared with UC (P < .05). RDI was 92.9% ± 12.1% and 93.6% ± 11.1% for intervention and UC, respectively (P = .69); the proportion of patients in the intervention versus UC who achieved ≥85% RDI was 81% and 85%, respectively (P = .44). The proportion of patients who had at least one dose reduction and/or delay was 38% intervention and 36% UC (P = .80). Among 72 women who received neoadjuvant chemotherapy, women randomly assigned to intervention were more likely to have a pCR than those randomly assigned to UC (53% v 28%; P = .037). CONCLUSION: Although a diet and exercise intervention did not affect RDI, the intervention was associated with a higher pCR in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative and triple-negative breast cancer undergoing neoadjuvant chemotherapy.

Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Effect of Exercise on Chemotherapy-Induced Peripheral Neuropathy Among Patients Treated for Ovarian Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among survivors of ovarian cancer. Currently, there is no effective treatment for CIPN. Objective: To evaluate the effect of a 6-month aerobic exercise intervention vs attention-control on CIPN among women treated for ovarian cancer in the Women's Activity and Lifestyle Study in Connecticut (WALC) to provide evidence to inform the guidelines and recommendations for prevention or treatment of CIPN. Design, Setting, and Participants: This prespecified secondary analysis evaluated the Women's Activity and Lifestyle Study in Connecticut (WALC), a multicentered, open-label, population-based, phase 3 randomized clinical trial of an aerobic exercise intervention vs attention control for CIPN in patients who were diagnosed with ovarian cancer. Only WALC participants who received chemotherapy were included in this analysis. Participants were randomized 1:1 to either a 6-month aerobic exercise intervention or to attention control. All analyses were conducted between September 2022 and January 2023. Interventions: The exercise intervention consisted of home-based moderate-intensity aerobic exercise facilitated by weekly telephone counseling from an American College of Sports Medicine/American Cancer Society-certified cancer exercise trainer. Attention control involved weekly health education telephone calls from a WALC staff member. Main Outcomes and Measure: Change in CIPN was the primary outcome in this secondary analysis. This outcome was represented by CIPN severity, which was self-measured by participants at baseline and 6 months using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, with a score range of 0 to 44. A mixed-effects model was used to assess the 6-month change in CIPN between the exercise intervention and attention control arms. Results: Of the 134 participants (all females; mean [SD] age, 57.5 [8.3] years) included in the analysis, 69 were in the exercise intervention arm and 65 were in the attention control arm. The mean (SD) time since diagnosis was 1.7 (1.0) years. The mean (SD) baseline CIPN scores were 8.1 (5.6) in the exercise intervention arm and 8.8 (7.9) in the attention control arm (P = .56). At 6 months, the self-reported CIPN score was reduced by 1.3 (95% CI, -2.3 to -0.2) points in the exercise intervention arm compared with an increase of 0.4 (95% CI, -0.8 to 1.5) points in the attention control arm. The between-group difference was -1.6 (95% CI, -3.1 to -0.2) points. The point estimate was larger among the 127 patients with CIPN symptoms at enrollment (-2.0; 95% CI, -3.6 to -0.5 points). Conclusions and Relevance: Findings of this secondary analysis of the WALC trial indicate that a 6-month aerobic exercise intervention vs attention control significantly improved self-reported CIPN among patients who were treated for ovarian cancer. While replication of the findings in other studies is warranted, incorporating referrals to exercise programs into standard oncology care could reduce CIPN symptoms and increase quality of life in patients with ovarian cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02107066.

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

Effect of a Home Health and Safety Intervention on Emergency Department Use in the Frail Elderly: A Prospective Observational Study.

INTRODUCTION: Geriatric patients are often frail and may lose independence through a variety of mechanisms including cognitive decline, reduced mobility, and falls. Our goal was to measure the effect of a multidisciplinary home health program that assessed frailty and safety and then coordinated ongoing delivery of community resources on short-term, all-cause emergency department (ED) utilization across three study arms that attempted to stratify frailty by fall risk. METHODS: Subjects became eligible for this prospective observational study via one of three pathways: 1) by visiting the ED after a fall (2,757 patients); 2) by self-identifying as at risk for falling (2,787); or 3) by calling 9-1-1 for a "lift assist" after falling and being unable to get up (121). The intervention consisted of sequential home visits by a research paramedic who used standardized assessments of frailty and risk of falling (including providing home safety guidance), and a home health nurse who aligned resources to address the conditions found. Outcomes of interest were all-cause ED utilization at 30, 60, and 90 days post-intervention compared with subjects who enrolled via the same study pathway but declined the study intervention (controls). RESULTS: Subjects in the fall-related ED visit arm were significantly less likely to have one or more subsequent ED encounters post-intervention than controls at 30 days (18.2% vs 29.2%, P<0.001); 60 days (27.5% vs 39.8%, P<0.001); and 90 days (34.6% vs 46.2%, P<0.001). In contrast, participants in the self-referral arm had no difference in ED encounters post-intervention compared to controls at 30, 60, or 90 days (P=0.30, 0.84, and 0.23, respectively). The size of the 9-1-1 call arm limited statistical power for analysis. CONCLUSION: A history of a fall requiring ED evaluation appeared to be a useful marker of frailty. Subjects recruited through this pathway experienced less all-cause ED utilization over subsequent months after a coordinated community intervention than without it. The participants who only self-identified as at risk for falling had lower rates of subsequent ED utilization than those recruited in the ED after a fall and did not significantly benefit from the intervention.

Randomized trial of exercise on cancer-related blood biomarkers and survival in women with ovarian cancer.

BACKGROUND: In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. METHODS: This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided. RESULTS: Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). CONCLUSIONS: Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.