Imputation-based Q-learning for optimizing dynamic treatment regimes with right-censored survival outcome.

Q-learning has been one of the most commonly used methods for optimizing dynamic treatment regimes (DTRs) in multistage decision-making. Right-censored survival outcome poses a significant challenge to Q-Learning due to its reliance on parametric models for counterfactual estimation which are subject to misspecification and sensitive to missing covariates. In this paper, we propose an imputation-based Q-learning (IQ-learning) where flexible nonparametric or semiparametric models are employed to estimate optimal treatment rules for each stage and then weighted hot-deck multiple imputation (MI) and direct-draw MI are used to predict optimal potential survival times. Missing data are handled using inverse probability weighting and MI, and the nonrandom treatment assignment among the observed is accounted for using a propensity-score approach. We investigate the performance of IQ-learning via extensive simulations and show that it is more robust to model misspecification than existing Q-Learning methods, imputes only plausible potential survival times contrary to parametric models and provides more flexibility in terms of baseline hazard shape. Using IQ-learning, we developed an optimal DTR for leukemia treatment based on a randomized trial with observational follow-up that motivated this study.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Dynamic impairment classification through arrayed comparisons.

The multivariate normative comparison (MNC) method has been used for identifying cognitive impairment. When participants' cognitive brain domains are evaluated regularly, the longitudinal MNC (LMNC) has been introduced to correct for the intercorrelation among repeated assessments of multiple cognitive domains in the same participant. However, it may not be practical to wait until the end of study for diagnosis. For example, in participants of the Multicenter AIDS Cohort Study (MACS), cognitive functioning has been evaluated repeatedly for more than 35 years. Therefore, it is optimal to identify cognitive impairment at each assessment, while the family-wise error rate (FWER) is controlled with unknown number of assessments in future. In this work, we propose to use the difference of consecutive LMNC test statistics to construct independent tests. Frequency modeling can help predict how many assessments each participant will have, so Bonferroni-type correction can be easily adapted. A chi-squared test is used under the assumption of multivariate normality, and permutation test is proposed where this assumption is violated. We showed through simulation and the MACS data that our method controlled FWER below a predetermined level.

Association Between Patient-Reported Symptoms of Dysphagia and Psychological Distress in Head and Neck Cancer Survivors.

OBJECTIVES: To describe the prevalence of and the association between patient-reported dysphagia and psychological distress (anxiety and depression) in head and neck cancer (HNC) survivors. SAMPLE & SETTING: 228 HNC survivors seen at an interprofessional survivorship clinic in Pittsburgh, PA, between October 2018 and January 2020. METHODS & VARIABLES: Dysphagia was evaluated using the Eating Assessment Tool. Anxiety and depression were measured using the Generalized Anxiety Disorder-7 and Patient Health Questionnaire-8, respectively. Descriptive statistics and multiple linear regression were performed. RESULTS: 70% (n = 159) of survivors reported problems with swallowing safely and efficiently. Twenty-seven survivors reported symptoms of major depression, 34 reported mild symptoms of anxiety, and 19 reported moderate to severe symptoms of anxiety and depression. After controlling for treatment modality, age, and stage, dysphagia was associated with increased symptoms of anxiety and depression. IMPLICATIONS FOR NURSING: Oncology nurses can inform their daily practice by implementing regular assessments for anxiety and depression in HNC survivors reporting symptoms of dysphagia.

Quality of life after radiation and transoral robotic surgery in advanced oropharyngeal cancer.

OBJECTIVES: Oropharyngeal squamous cell carcinoma (OPSCC) treatment results in impaired swallowing and quality of life (QOL). We analyzed a cross-section of advanced stage OPSCC patients treated with multimodal therapies at our Survivorship Clinic to investigate treatment factors associated with QOL. METHODS: Retrospective analysis of patient-reported outcomes (PROMs) after primary OPSCC treatment using AJCC seventh edition staging. RESULTS: A total of 73 patients were included (90.1% human papillomavirus positive [HPV+]). There were no QOL differences between robotic surgery with radiation ± chemotherapy patients (n = 29) and those treated by radiation ± chemotherapy (n = 44). Radiation field analysis demonstrated significant correlations between increasing doses to larynx and contralateral parotid and submandibular gland and worse swallowing as measured by the Eating Assessment Tool-10 (P = .02; P = .01; P = .01). CONCLUSIONS: In advanced, mostly HPV+, OPSCC, we did not find clinically significant differences between QOL PROMs between surgical and radiation ± chemotherapy treatment groups. This highlights the need for continued therapy de-escalation along with improved interventions for treatment related toxicities. LEVEL OF EVIDENCE: 4.

Toughness and Durability of Interfaces in Dissimilar Adhesive Joints of Aluminum and Carbon-Fiber-Reinforced Thermoplastics.

The toughness and the durability under a high humidity condition of the interfaces in dissimilar adhesive joints of carbon-fiber-reinforced thermoplastic with a polyamide-6 matrix and Al alloy were evaluated by two test methods, in which a tensile opening load was applied to the specimens to cleave the interfaces apart in two different ways. In the double cantilever beam (DCB) test, the specimens were continuously pulled apart at a constant velocity, while in the wedge test, the specimens are pulled apart at a constant displacement. The crack growth along the interface in the DCB test was dynamically monitored with the assistance of mechanoluminescence for the accurate detection of the phenomena at the crack tip. The wedge test was employed for the evaluation of the durability of the interfaces under high humidity conditions. It was found that the adhesive joints were failed by various failure modes depending on the surface pretreatment and environmental conditions. Throughout the work, discussion was made concerned with the interfacial structures and the adhesion mechanism of dissimilar adhesive joints.

Neck Disability and Swallowing Function in Posttreatment Head and Neck Cancer Patients.

OBJECTIVE: To examine the relationship between symptoms of neck disability and swallowing dysfunction among head and neck cancer (HNC) survivors. STUDY DESIGN: Cross-sectional analysis. SETTING: Single-center, university-affiliated HNC survivorship clinic. SUBJECTS AND METHODS: Survivors' patient-reported symptoms of neck disability and swallowing dysfunction were prospectively collected from March 2017 to May 2018. Neck disability and swallowing dysfunction were measured using the Neck Disability Index and Eating Assessment Tool (EAT-10), respectively. Linear regression was used to analyze the association between neck disability and swallowing dysfunction. RESULTS: A total of 179 survivors, predominantly male (n = 130, 72.6%) with an average age of 64.64 ± 9.91 years, were included in the analysis. Primary cancer sites were oropharynx (n = 85, 47.5%), oral cavity (n = 59, 33.0%), and larynx/hypopharynx (n = 35, 19.5%). Mean EAT-10 score was 10.07 ± 10.89 (range = 0-40; >2 indicative of swallowing dysfunction). Survivors treated for early stage cancer had lower EAT-10 scores than those with advanced stage (early = 3.55 ± 7.46; advanced = 11.95 ± 11.02, P < .001). After controlling for age, time since treatment, American Joint Committee on Cancer stage, and treatment modality, the EAT-10 score for patients with mild neck disability was 6.88 (95% confidence interval [CI], 3.71-10.06; P < .001) points higher than those without neck disability, and the score for those with moderate-complete neck disability was 13.65 (95% CI, 9.47-17.83; P < .001) points higher than those without neck disability. CONCLUSIONS: Swallowing dysfunction is a commonly recognized effect of HNC treatment. The prevalence and burden of neck disability are shown to be highly correlated with swallowing dysfunction. These results support the need for comprehensive, multidisciplinary rehabilitation interventions for patients with HNC.

Health literacy: Impact on quality of life in head and neck cancer survivors.

OBJECTIVES: Although inadequate health literacy has been shown to impact health outcomes in other cancers, little is known about its impact in head and neck cancer (HNC). This study aimed to determine the prevalence and predictors of inadequate health literacy and evaluate the association between health literacy and quality of life (QOL) in HNC survivors. METHODS: We conducted a retrospective analysis of HNC survivors evaluated in a multidisciplinary HNC survivorship clinic. Survivors had to be ≥1-year postcompletion of treatment to be included in the analysis. Health literacy was assessed via self-report with the Brief Health Literacy Screen (score <10 indicating inadequate health literacy), and QOL was measured using the University of Washington QOL questionnaire. Linear regression with robust standard errors was utilized to evaluate the association between health literacy and QOL. RESULTS: Of the 218 survivors evaluated, 13.8% (n = 30) demonstrated inadequate health literacy. After adjusting for age, marital status, site, stage, treatment modality, and years since treatment completion, social-emotional QOL scores for survivors with adequate health literacy were estimated to be 10.67 points higher than those with inadequate health literacy (P = .013). Health literacy was not significantly associated with physical QOL after adjusting for covariates (P = .130). CONCLUSION: Inadequate health literacy is associated with a lower social QOL in HNC survivors, and among those with inadequate health literacy, interventions to ameliorate the impact on QOL are needed. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2354-2359, 2020.

Impact of Neck Disability on Health-Related Quality of Life among Head and Neck Cancer Survivors.

OBJECTIVE: Although neck impairment has been described following surgical resection, limited studies have investigated its prevalence in nonsurgical treatment. The purpose of this study is to determine the prevalence and predictors of neck disability following head and neck cancer (HNC) treatment and to explore its association with quality of life (QOL). STUDY DESIGN: Cross-sectional study. SETTING: HNC survivorship clinic. SUBJECTS AND METHODS: We identified 214 survivors who completed treatment ≥1 year prior to evaluation in the clinic. Self-reported neck impairment was measured using the Neck Disability Index. QOL was measured using the University of Washington QOL Questionnaire, with physical and social subscale scores calculated. Regression analysis and trend tests were employed to explore associations. RESULTS: Over half of survivors (54.2%) reported neck disability. The odds of neck disability in survivors who received nonsurgical treatment and those who received surgery plus adjuvant treatment were 3.46 and 4.98 times higher compared to surgery alone (P = .008, P = .004). Survivors who underwent surgery only had higher physical and social QOL than those who received nonsurgical treatment (physical QOL: P < .001, social QOL: P = .023) and those who received surgery plus adjuvant treatment (physical QOL: P < .001, social QOL: P = .039). CONCLUSION: This study revealed a high prevalence of neck disability following nonsurgical treatment. While neck disability is an established sequela of surgical resection, the impact of nonsurgical treatment has gone unrecognized. Early identification and intervention to prevent progression of neck disability are crucial to optimize QOL.

Understanding financial toxicity in head and neck cancer survivors.

OBJECTIVES: (1) Describe financial toxicity (FT) in head and neck cancer (HNC) survivors and assess its association with personal/health characteristics and health-related quality of life (HRQOL); (2) examine financial coping mechanisms (savings/loans); (3) assess relationship between COmprehensive Score for financial Toxicity (COST) and Financial Distress Questionnaire (FDQ). PATIENTS AND METHODS: Cross-sectional survey from January - April 2018 of insured patients at a tertiary multidisciplinary HNC survivorship clinic who completed primary treatment for squamous cell carcinoma of the oral cavity, oropharynx, or larynx/hypopharynx. RESULTS: Of 104 survivors, 30 (40.5%) demonstrated high FT. Patients with worse FT were more likely (1) not married (COST, 25.33 ±â€¯1.87 vs. 30.61 ±â€¯1.34, p = 0.008); (2) of lower education levels (COST, 26.12 ±â€¯1.47 vs. 34.14 ±â€¯1.47, p < 0.001); and (3) with larynx/hypopharynx primaries (COST, 22.86 ±â€¯2.28 vs. 30.27 ±â€¯1.50 vs. 32.72 ±â€¯1.98, p = 0.005). Younger age (4.23, 95%CI 2.20 to 6.26, p < 0.001), lower earnings at diagnosis (1.17, 95%CI 0.76 to 1.58, p < 0.001), and loss in earnings (-1.80, 95%CI -2.43 to -1.16, p < 0.001) were associated with worse FT. COST was associated with HRQOL (0.08, p = 0.03). Most survivors (63/102, 60%) reported using savings and/or loans. Worse FT was associated with increased likelihood of using more mechanisms (COST, OR1.06, 95%CI 1.02 to 1.10, p = 0.004). Similar results were found with FDQ. CONCLUSIONS: We found differences in FT by primary site, with worst FT in larynx/hypopharynx patients. This finding illuminates potential site-specific factors, e.g. workplace discrimination or inability to return to work, that may contribute to increased risk. FDQ correlates strongly with COST, encouraging further exploration as a clinically-meaningful screening tool.

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes.

Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Furthermore, high-resolution multiple reaction monitoring (MRM-HR), a targeted proteomic approach, was utilized to compare the expressions of pre-selected DMEs between human livers and the cell lines. In general, the SWATH quantifications were in good agreement with the MRM-HR analysis. Over 3000 protein groups were quantified in the cells and human livers, and the proteome profiles of human livers significantly differed from the cell lines. Among the 101 DMEs quantified with MRM-HR, most were expressed at substantially lower levels in the cell lines. Thus, appropriate caution must be exercised when using these cell lines for the study of hepatic drug metabolism and toxicity.

Reversible Protonic Doping in Poly(3,4-Ethylenedioxythiophene).

In this study, poly(3,4-ethylenedioxythiophene), a benchmark-conducting polymer, was doped by protons. The doping and de-doping processes, using protonic acid and a base, were fully reversible. We predicted possible doping sites along the polymer chain using density functional theory (DFT) calculations. This study sheds potential light and understanding on the molecular design of highly conductive organic materials.

NaHCO3-enhanced hydrogen production from water with Fe and in situ highly efficient and autocatalytic NaHCO3 reduction into formic acid.

We report a highly efficient water splitting for CO2 reduction into formic acid with a commercially available metal of Fe powder without adding any other catalyst. An excellent formic acid yield of more than 90% was attained.

No catalyst addition and highly efficient dissociation of H2O for the reduction of CO2 to formic acid with Mn.

The "greenhouse effect" caused by the increasing atmospheric CO2 level is becoming extremely serious, and thus, the reduction of CO2 emissions has become an extensive, urgent, and long-term task. The dissociation of water for CO2 reduction with solar energy is regarded as one of the most promising methods for the sustainable development of the environment and energy. However, a high solar-to-fuel efficiency keeps a great challenge. In this work, the first observation of a highly effective, highly selective, and robust system of dissociating water for the reduction of carbon dioxide (CO2) into formic acid with metallic manganese (Mn) is reported. A considerably high formic acid yield of more than 75% on a carbon basis from NaHCO3 was achieved with 98% selectivity in the presence of simple commercially available Mn powder without the addition of any catalyst, and the proposed process is exothermic. Thus, this study may provide a promising method for the highly efficient dissociation of water for CO2 reduction by combining solar-driven thermochemistry with the reduction of MnO into Mn.