Causal Selection of Covariates in Regression Calibration for Mismeasured Continuous Exposure.

Regression calibration as developed by Rosner, Spiegelman, and Willett is used to adjust the bias in effect estimates due to measurement error in continuous exposures. The method involves two models: a measurement error model relating the mismeasured exposure to the true (or gold-standard) exposure and an outcome model relating the mismeasured exposure to the outcome. However, no comprehensive guidance exists for determining which covariates should be included in each model. In this article, we investigate the selection of the minimal and most efficient covariate adjustment sets under a causal inference framework. We show that to address the measurement error, researchers must adjust for, in both measurement error and outcome models, any common causes (1) of true exposure and the outcome and (2) of measurement error and the outcome. We also show that adjusting for so-called prognostic variables that are independent of true exposure and measurement error in the outcome model, may increase efficiency, while adjusting for any covariates that are associated only with true exposure generally results in efficiency loss in realistic settings. We apply the proposed covariate selection approach to the Health Professional Follow-up Study dataset to study the effect of fiber intake on cardiovascular disease. Finally, we extend the originally proposed estimators to a nonparametric setting where effect modification by covariates is allowed.

Ecological restoration for eutrophication mitigation in urban interconnected water bodies: Evaluation, variability and strategy.

Many urban water bodies grapple with low flow flux and weak hydrodynamics. To address these issues, projects have been implemented to form integrated urban water bodies via interconnecting artificial lake or ponds with rivers, but causing pollution accumulation downstream and eutrophication. Despite it is crucial to assess eutrophication, research on this topic in urban interconnected water bodies is limited, particularly regarding variability and feasible strategies for remediation. This study focused on the Loucun river in Shenzhen, comprising an pond, river and artificial lake, evaluating water quality changes pre-(post-)ecological remediation and establishing a new method for evaluating the water quality index (WQI). The underwater forest project, involving basement improvement, vegetation restoration, and aquatic augmentation, in the artificial lake significantly reduced total nitrogen (by 43.58%), total phosphorus (by 79.17%) and algae density (by 36.90%) compared to pre-remediation, effectively controlling algal bloom. Rainfall, acting as a variable factor, exacerbated downstream nutrient accumulation, increasing total phosphorus by 4.56 times and ammonia nitrogen by 1.30 times compared to the dry season, and leading to algal blooms in the non-restoration pond. The improved WQI method effectively assesses water quality status. The interconnected water body exhibits obvious nutrient accumulation in downstream regions. A combined strategy that reducing nutrient and augmenting flux was verified to alleviate accumulation of nutrients downstream. This study provides valuable insights into pollution management strategies for interconnected pond-river-lake water bodies, offering significant reference for nutrient mitigation in such urban water bodies.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy. METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102. FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache. INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease. FUNDING: AbbVie.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

Fear of progression and its associated factors in parents of children undergoing cancer treatment: A cross-sectional study.

OBJECTIVE: Fear of progression (FoP) is a common psychosocial problem among adult cancer patients, but data on parents of children undergoing cancer treatment are scarce. This study aimed to determine the prevalence of FoP in parents of children undergoing cancer treatment and explore the associated factors. METHODS: Overall, 285 parents of children undergoing cancer treatment were recruited from three general hospitals in China. FoP in the parents was assessed using the Chinese version of the Fear of Progression Questionnaire-parent version (FoP-Q-SF/PR). Other questionnaires included the Self-Compassion Scale, Pittsburgh Sleep Quality Index, Posttraumatic Stress Disorder Checklist-Civilian Version, and items on socio-demographic and medical characteristics. Pearson correlation and multiple linear regression analysis were used to identify factors associated with FoP. RESULTS: A total of 75.1% of the participants showed dysfunctional levels of FoP. The mean FoP-Q-SF/PR score was 39.98 (standard deviation = 9.18). Parental FoP was significantly associated with a shorter time since diagnosis, lower levels of self-compassion, poor sleep quality, and severe posttraumatic stress symptoms (Adjusted R Squared = 0.369, F = 12.838, p < 0.01). CONCLUSIONS: FoP is a frequently reported problem among parents of children undergoing cancer treatment. In this cohort, parents of children with a shorter time since cancer diagnosis were at higher risk of suffering from FoP. Interventions to enhance self-compassion, improve sleep quality, and mitigate posttraumatic stress symptoms may help with the psychological adjustment and well-being of parents whose children are undergoing cancer treatment.

A maximum likelihood approach to power calculations for stepped wedge designs of binary outcomes.

In stepped wedge designs (SWD), clusters are randomized to the time period during which new patients will receive the intervention under study in a sequential rollout over time. By the study's end, patients at all clusters receive the intervention, eliminating ethical concerns related to withholding potentially efficacious treatments. This is a practical option in many large-scale public health implementation settings. Little statistical theory for these designs exists for binary outcomes. To address this, we utilized a maximum likelihood approach and developed numerical methods to determine the asymptotic power of the SWD for binary outcomes. We studied how the power of a SWD for detecting risk differences varies as a function of the number of clusters, cluster size, the baseline risk, the intervention effect, the intra-cluster correlation coefficient, and the time effect. We studied the robustness of power to the assumed form of the distribution of the cluster random effects, as well as how power is affected by variable cluster size. % SWD power is sensitive to neither, in contrast to the parallel cluster randomized design which is highly sensitive to variable cluster size. We also found that the approximate weighted least square approach of Hussey and Hughes (2007, Design and analysis of stepped wedge cluster randomized trials. Contemporary Clinical Trials 28, 182-191) for binary outcomes under-estimates the power in some regions of the parameter spaces, and over-estimates it in others. The new method was applied to the design of a large-scale intervention program on post-partum intra-uterine device insertion services for preventing unintended pregnancy in the first 1.5 years following childbirth in Tanzania, where it was found that the previously available method under-estimated the power.

A modified partial likelihood score method for Cox regression with covariate error under the internal validation design.

We develop a new method for covariate error correction in the Cox survival regression model, given a modest sample of internal validation data. Unlike most previous methods for this setting, our method can handle covariate error of arbitrary form. Asymptotic properties of the estimator are derived. In a simulation study, the method was found to perform very well in terms of bias reduction and confidence interval coverage. The method is applied to data from the Health Professionals Follow-Up Study (HPFS) on the effect of diet on incidence of Type II diabetes.

Rapid Aerobic Inactivation and Facile Removal of Escherichia coli with Amorphous Zero-Valent Iron Microspheres: Indispensable Roles of Reactive Oxygen Species and Iron Corrosion Products.

Zero valent iron (ZVI) is recently regarded as a promising alternative for water disinfection, but still suffers from low efficiency. Herein we demonstrate that amorphous zerovalent iron microspheres (A-mZVI) exhibit both higher inactivation rate and physical removal efficiency for the disinfection of Escherichia coli than conventional crystalline nanoscale ZVI (C-nZVI) under aerobic condition. The enhanced E. coli inactivation performance of A-mZVI was mainly attributed to more reactive oxygen species (ROSs), especially free •OH, generated by the accelerated iron dissolution and molecular oxygen activation in bulk solution. In contrast, C-nZVI preferred to produce surface bound •OH, and its bactericidal ability was thus hampered by the limited physical contact between C-nZVI and E. coli. More importantly, hydrolysis of dissolved iron released from A-mZVI produced plenty of loose FeOOH to wrap E. coli, increasing the dysfunction of E. coli membrane. Meanwhile, this hydrolysis process lowered the stability of E. coli colloid and caused its rapid coagulation and sedimentation, favoring its physical removal. These findings clarify the indispensable roles of ROSs and iron corrosion products during the ZVI disinfection, and also provide a promising disinfection material for water treatment.

Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short-Term Exposure to Moderate Noise.

Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks) and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons.

Mammographic density and breast cancer risk: a mediation analysis.

BACKGROUND: High mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently. METHODS: Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses' Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD. RESULTS: In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD. CONCLUSIONS: Percent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development.

Quantifying risk over the life course - latency, age-related susceptibility, and other time-varying exposure metrics.

Identification of the latency period and age-related susceptibility, if any, is an important aspect of assessing risks of environmental, nutritional, and occupational exposures. We consider estimation and inference for latency and age-related susceptibility in relative risk and excess risk models. We focus on likelihood-based methods for point and interval estimation of the latency period and age-related windows of susceptibility coupled with several commonly considered exposure metrics. The method is illustrated in a study of the timing of the effects of constituents of air pollution on mortality in the Nurses' Health Study. Copyright © 2016 John Wiley & Sons, Ltd.

The association of long-term exposure to PM2.5 on all-cause mortality in the Nurses' Health Study and the impact of measurement-error correction.

BACKGROUND: Long-term exposure to particulate matter less than 2.5 µm in diameter (PM2.5) has been consistently associated with risk of all-cause mortality. The methods used to assess exposure, such as area averages, nearest monitor values, land use regressions, and spatio-temporal models in these studies are subject to measurement error. However, to date, no study has attempted to incorporate adjustment for measurement error into a long-term study of the effects of air pollution on mortality. METHODS: We followed 108,767 members of the Nurses' Health Study (NHS) 2000-2006 and identified all deaths. Biennial mailed questionnaires provided a detailed residential address history and updated information on potential confounders. Time-varying average PM2.5 in the previous 12-months was assigned based on residential address and was predicted from either spatio-temporal prediction models or as concentrations measured at the nearest USEPA monitor. Information on the relationships of personal exposure to PM2.5 of ambient origin with spatio-temporal predicted and nearest monitor PM2.5 was available from five previous validation studies. Time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 percent confidence intervals (95%CI) for each 10 µg/m(3) increase in PM2.5. Risk-set regression calibration was used to adjust estimates for measurement error. RESULTS: Increasing exposure to PM2.5 was associated with an increased risk of mortality, and results were similar regardless of the method chosen for exposure assessment. Specifically, the multivariable adjusted HRs for each 10 µg/m(3) increase in 12-month average PM2.5 from spatio-temporal prediction models were 1.13 (95%CI:1.05, 1.22) and 1.12 (95%CI:1.05, 1.21) for concentrations at the nearest EPA monitoring location. Adjustment for measurement error increased the magnitude of the HRs 4-10% and led to wider CIs (HR = 1.18; 95%CI: 1.02, 1.36 for each 10 µg/m(3) increase in PM2.5 from the spatio-temporal models and HR = 1.22; 95%CI: 1.02, 1.45 from the nearest monitor estimates). CONCLUSIONS: These findings support the large body of literature on the adverse effects of PM2.5, and suggest that adjustment for measurement error be considered in future studies where possible.

Maintenance Risankizumab Sustains Induction Response in Patients with Crohn's Disease in a Randomized Phase 3 Trial.

BACKGROUND AND AIMS: Durable clinical remission, endoscopic healing, and biomarker normalization are key treatment goals for Crohn's disease. The selective anti-interleukin-23 p19 inhibitor risankizumab has demonstrated efficacy and safety in moderately to severely active Crohn's disease. This post-hoc analysis of data from the pivotal risankizumab maintenance study assessed whether risankizumab maintenance therapy sustained the clinical and endoscopic outcomes achieved with risankizumab induction therapy. METHODS: We evaluated 462 patients who achieved a clinical response to risankizumab intravenous induction treatment and were re-randomized to receive subcutaneous risankizumab 360 mg, subcutaneous risankizumab 180 mg, or placebo [withdrawal] every 8 weeks for 52 weeks in the randomized, controlled FORTIFY maintenance study. Maintenance of clinical, endoscopic, and biomarker endpoints at week 52 among patients who achieved these endpoints after 12 weeks of induction treatment was evaluated. RESULTS: A significantly higher proportion of patients receiving maintenance treatment with risankizumab 360 or 180 mg compared with placebo [withdrawal] maintained Crohn's Disease Activity Index remission [68.6%, 70.8%, vs 56.3%; p < 0.05], stool frequency/abdominal pain remission [69.2%, 64.1%, vs 50.5%; p < 0.01], endoscopic response [70.2%, 68.2%, vs 38.4%; p < 0.001], endoscopic remission [74.4%, 45.5%, vs 23.9%; p < 0.05], and Simple Endoscopic Score for Crohn's Disease of 0-2 [65.5%, 36.7%, vs 21.9%]. Most patients [56.8-83.3%] who achieved normalized faecal calprotectin or C-reactive protein during induction sustained them with maintenance risankizumab. CONCLUSIONS: Subcutaneous risankizumab maintenance therapy results in durable improvement in clinical and endoscopic outcomes over 1 year in patients with moderately to severely active Crohn's disease. CLINICAL TRIAL REGISTRATION NUMBER: NCT03105102.

Can efficiency be gained by correcting for misclassification?

This paper considers 2×2 tables arising from case-control studies in which the binary exposure may be misclassified. We found circumstances under which the inverse matrix method provides a more efficient odds ratio estimator than the naive estimator. We provide some intuition for the findings, and also provide a formula for obtaining the minimum size of a validation study such that the variance of the odds ratio estimator from the inverse matrix method is smaller than that of the naive estimator, thereby ensuring an advantage for the misclassification corrected result. As a corollary of this result, we show that correcting for misclassification does not necessarily lead to a widening of the confidence intervals, but, rather, in addition to producing a consistent estimate, can also produce one that is more efficient.

Effect of risankizumab on health-related quality of life in patients with Crohn's disease: results from phase 3 MOTIVATE, ADVANCE and FORTIFY clinical trials.

BACKGROUND: Crohn's disease has a substantial negative impact on health-related quality of life (HRQoL). AIM: To examine the effects of risankizumab on HRQoL in Crohn's disease METHODS: We analysed data from patients with Crohn's disease from 12-week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52-week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-item Short Form Health Survey (SF-36), EuroQol 5-Dimension-5-Level (EQ-5D-5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52. RESULTS: At week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT-F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p < 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF-36 physical and mental component summary scores, EQ-5D-5L and activity impairment within work productivity measures. CONCLUSIONS: Risankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease-specific and general patient-reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

Efficacy, Safety, Patient Experience, and Tolerability of Risankizumab Administered by On-Body Injector for Moderate to Severe Crohn's Disease.

INTRODUCTION: In patients with moderate to severe Crohn's disease (CD), intravenous induction and subcutaneous maintenance dosing with risankizumab was efficacious and well tolerated. Long-term management of CD via self-administration of risankizumab using an on-body injector (OBI) may improve treatment adherence through convenience and ease of use. METHODS: Within the FORTIFY maintenance study, 46 patients from the United States (US) sites participated in an open-label extension Substudy and received 180 mg or 360 mg risankizumab delivered subcutaneously via OBI [360 mg (2.4 mL, 150 mg/mL) or 180 mg (1.2 mL, 150 mg/mL)]. At the Week 0 visit, patients were trained (pre-injection) by site staff, using Instructions for Use (IFU) and a training video, to self-administer risankizumab at Weeks 0 (on site), 8 (at home), and 16 (on site). Key objectives of the Substudy 4 were to assess OBI usability (observer rating of successful self-administration), hazard-free self-injection at Weeks 0 and 16, and patient rating of acceptability using the Self-Injection Assessment Questionnaire (SIAQ) at Weeks 0, 8, and 16. Additionally, the proportion of patients in clinical remission (CD Activity Index < 150) was collected at Weeks 0 and 16. RESULTS: All patients successfully self-administered risankizumab via OBI, including two patients who successfully self-administered with a second OBI (i.e., required two injection attempts). Acceptability of self-injection was high. Two patients (n = 2) experienced a use-related hazard. Stable clinical remission was observed with both risankizumab doses. Two patients experienced injection site reactions; neither was related to the OBI per investigator's assessment. Two device-related adverse events related to topical adhesive reactions were reported, both mild and resolved. No new safety risks were observed. CONCLUSION: The efficacy and safety of maintenance risankizumab delivered via OBI and OBI usability support the use of this device in patients with moderate to severe CD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03105102 (FORTIFY).

ERCC1 is a potential biomarker for predicting prognosis, immunotherapy, chemotherapy efficacy, and expression validation in HER2 over-expressing breast cancer.

Objective: To investigate the relationship between Excision repair cross-complementation 1 (ERCC1) expression, clinicopathological features, and breast cancer prognosis in patients treated with trastuzumab. Further, we aim to explore the immune status of ERCC1 in breast cancer. Methods: The data were retrieved from publicly available databases like the Cancer Genome Atlas, Therapeutically Applicable Research to Generate Effective Treatments, and the Genotype-Tissue Expression. The data was used to perform differential expression analyses between tumor and normal tissues in pan-cancers, immune-related analysis, homologous recombination deficiency (HRD), tumor mutation burden, and microsatellite instability. A total of 210 patients with HER2 over-expressing breast cancer from the Fourth Hospital of Hebei Medical University between January 2013 to December 2015 were enrolled in the study. Ten adjacent normal tissues were used to study the expression pattern of ERCC1 in normal tissues. Immunohistochemistry was performed to study ERCC1 expression and immune cell infiltration in different status of ERCC1 expression. Further, the correlation between ERCC1 expression, immune cell infiltration clinicopathological features, and the prognosis of patients with breast cancer was analyzed. Results: The immune analysis revealed a significant correlation between CD8+ T cell, CD4+ T cell, T helper cell, macrophages, mast cells, and ERCC1 expression. Spearman analysis show that ERCC1 expression is related to macrophages and T cells. A close correlation was observed between increased ERCC1 expression and high tumor immune dysfunction and exclusion (TIDE) score as well as HRD. The results revealed a significant correlation among ERCC1, chemotherapy and estrogen receptor (ER; P < 0.05) expression. Univariate survival analysis revealed a significant correlation (P < 0.05) between that ERCC1 and ER expression, blood vessel invasion, and disease-free survival (DFS). ERCC1 and ER expression, tumor size, blood vessel invasion, pathological type, and lymph node metastases significantly correlated (P < 0.05) with overall survival in patients. Multivariate regression analysis revealed that ERCC1 expression and chemotherapy were independent factors that influence DFS. ERCC1 expression and vascular tumor thrombus were independent influencing factors that influence OS. Conclusion: A correlation was observed between high ERCC1 expression and poor patient prognosis. High ERCC1 expression also influences the efficacy of immunotherapy and chemotherapy.

The complete mitochondrial genome of Comaster schlegelii (Crinoidea, Comatulida).

Comaster schlegelii, belonging to the family Comatulidae, is a variable feather star distributed in the Pacific Ocean. The complete mitochondrial genome of this species was 15,887 bp in length, consisting of 13 protein-coding genes, 22 transport RNA genes, two ribosomal RNA genes and one control region. The whole mitochondrial genome of C. schlegelii had a high AT content of 72.73%. The phylogenetic relationship was reconstructed with 16 relevant echinoderms, which revealed C. schlegelii was closely clustered with Anneissia pinguis in the family Comatulidae.

Membrane disruption boosts iron overload and endogenous oxidative stress to inactivate Escherichia coli by nanoscale zero-valent iron.

The inactivation of microorganisms by nanoscale zero-valent iron (nZVI) was extensively reported, but what happens inside the cells is rarely explored. Herein, we revealed that nZVI caused the drastic increase of intracellular iron concentrations, which subsequently catalyzed the Haber-Weiss reaction to produce high levels of endogenous reactive oxygen species (ROSs) and inactivated E. coli cells by oxidative damage of DNA, evidenced by the significantly higher inactivation efficiencies of E. coli mutant strains deficient in iron uptake regulation and DNA repair than the parental strain. The intracellular iron levels, endogenous ROSs levels and the inactivation efficiencies of E. coli were positively correlated. The permeabilized cytomembrane due to the close contact between nZVI and E. coli was responsible for the iron overload. This work demonstrates experimentally for the first time that nZVI causes iron overload and endogenous oxidative stress to inactivate E. coli, thus deepening our knowledge of the nZVI antimicrobial mechanism.

Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3ß activation and proteasome inhibition.

Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. Iron dyshomeostasis and peroxidation damage of neurons in some particular brain regions are closely related to a wide range of neurodegenerative diseases known as "tauopathies," in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated glycogen synthase kinase-3ß (GSK-3ß) is responsible for the abnormal hyperphosphorylation of tau. More importantly, proteasome inhibition can exacerbate tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.