IMSC-DERIVED EXTRACELLULAR VESICLES ATTENUATE LPS-INDUCED LUNG INJURY AND ENDOTOXEMIA IN MICE.

INTRODUCTION: We hypothesized extracellular vesicles (EVs) from preconditioned human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) attenuate LPS-induced acute lung injury (ALI) and endotoxemia. METHODS: iMSCs were incubated with cell stimulation cocktail (CSC) and EVs were isolated. iMSC-EVs were characterized by size and EV markers. Bio-distribution of intratracheal (IT), intravenous and intraperitoneal injection of iMSC-EVs in mice was examined using IVIS. Uptake of iMSC-EVs in lung tissue, alveolar macrophages and RAW264.7 cells was also assessed. C57BL/6 mice were treated with IT/IP iMSC-EVs or vehicle ± IT/IP LPS to induce ALI/ARDS and endotoxemia. Lung tissues, plasma and BALF were harvested at 24 h. Lung histology, BALF neutrophil/macrophage, cytokine levels and total protein concentration were measured to assess ALI and inflammation. Survival studies were performed using IP LPS in mice for three days. RESULTS: iMSC-EV route of administration resulted in differential tissue distribution. iMSC-EVs were taken up by alveolar macrophages in mouse lung and cultured RAW264.7 cells. IT LPS-treated mice demonstrated marked histologic ALI, increased BALF neutrophils/macrophages and protein, increased BALF and plasma TNF-α/IL-6 levels. These parameters were attenuated by 2 h pre- or 2 h post-treatment with IT iMSC-EVs in ALI mice. Interestingly, the IT LPS-induced increase in IL-10 was augmented by iMSC-EVs. Mice treated with IP LPS showed increases in TNF-α and IL-6 that were downregulated by iMSC-EVs and LPS-induced mortality was ameliorated by iMSC-EVs. Administration of IT iMSC-EVs 2 h after LPS down-regulated the increase in pro-inflammatory cytokines (TNF-α/IL-6) by LPS and further increased IL-10 levels. CONCLUSIONS: iMSC-EVs attenuate the inflammatory effects of LPS on cytokine levels in ALI and IP LPS in mice. LPS-induced mortality was improved with administration of iMSC-EVs.

Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

Pregnancy-adapted YEARS Algorithm: A Retrospective Analysis.

Introduction: Pulmonary embolism (PE) is an imperative diagnosis to make given its associated morbidity. There is no current consensus in the initial workup of pregnant patients suspected of a PE. Prospective studies have been conducted in Europe using a pregnancy-adapted YEARS algorithm, which showed safe reductions in computed tomography pulmonary angiography (CTPA) imaging in pregnant patients suspected of PE. Our objective in this study was 1) to measure the potential avoidance of CTPA use in pregnant patients if the pregnancy-adapted YEARS algorithm had been applied and 2) to serve as an external validation study of the use of this algorithm in the United States. Methods: This study was a single-system retrospective chart analysis. Criteria for inclusion in the cohort consisted of keywords: pregnant; older than 18; chief complaints of shortness of breath, chest pain, tachycardia, hemoptysis, deep vein thromboembolism (DVT), and D-dimer-from January 1, 2019- May 31,2022. We then analyzed this cohort retrospectively using the pregnancy-adapted YEARS algorithm, which includes clinical signs of a DVT, hemoptysis, and PE as the most likely diagnosis with a D-dimer assay. Patients within the cohort were then subdivided into two categories: aligned with the YEARS algorithm, or not aligned with the YEARS algorithm. Patients who did not receive a CTPA were analyzed for a subsequent diagnosis of a PE or DVT within 30 days. Results: A total of 74 pregnant patients were included in this study. There was a PE prevalence of 2.7% (two patients). Of the 36 patients who did not require imaging by the algorithm, seven CTPA were performed. Of the patients who did not receive an initial CTPA, zero were diagnosed with PE or DVT within a 30-day follow-up. In total, 85.1% of all the patients in this study were treated in concordance with the pregnancy-adapted YEARS algorithm. Conclusion: The use of the pregnancy-adapted YEARS algorithm could have resulted in decreased utilization of CTPA in the workup of PE in pregnant patients, and the algorithm showed similar reductions compared to prospective studies done in Europe. The pregnancy-adapted YEARS algorithm was also shown to be similar to the clinical rationale used by clinicians in the evaluation of pregnant patients, which indicates its potential for widespread acceptance into clinical practice.

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice.

Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-ß and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model.

Exploring the impact of the New York State repeal of nonmedical vaccination exemptions on student enrollment, absenteeism, and school workload: Perspectives from a survey of school administrators.

In June 2019, New York State (NYS) adopted Senate Bill 2994A eliminating nonmedical vaccine exemptions from school entry laws. Since student noncompliance with the law required school exclusion, we sought to evaluate the law's effects on student enrollment and absenteeism, and school workloads related to its implementation. In November 2019, we sent an electronic survey to NYS (excluding New York City) schools. Due to the COVID-19 pandemic, outreach was curtailed in March 2020 with 525 (14%) of 3,759 eligible schools responding. To account for non-response, results were analyzed using inverse probability weighting. After weighting, 39% (95% CI: 34%, 44%) of schools reported enrollment changes and 31% (95% CI: 26%, 36%) of schools reported absenteeism related to the law. In addition, 95% (95% CI: 93%, 98%) of schools reported holding meetings and/or preparing correspondence about the law, spending a mean of 14 (95% CI: 11, 18) hours on these communication efforts. Schools in the highest pre-mandate nonmedical exemption tertile (vs. lowest) were more likely to report enrollment and absenteeism changes, and higher workloads. While our results should be interpreted with caution, changes in student enrollment, absenteeism, and school workloads may represent important considerations for policymakers planning similar legislation.

Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. METHODS: In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. RESULTS: Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. CONCLUSION: Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.Trial Registration: NCT03700320.

Effectiveness of a Multi-component Delirium Prevention Program Implemented on General Medicine Hospital Units: an Interrupted Time Series Analysis.

BACKGROUND: Delirium is among the most prevalent harmful events in hospitals that is associated with an elevated risk for severe outcomes such as functional decline, falls, longer length of stay, and increased mortality. OBJECTIVE: To evaluate the impact of the implementation of a multi-component delirium program on the prevalence of delirium and the incidence of falls among patients staying on general medicine inpatient hospital units. DESIGN: A pre-post intervention study using retrospective chart abstraction and interrupted time series analysis. COHORT: Patients were selected from adult patients that stayed at least 1 day on one of the five general medicine units in a large community hospital in Ontario, Canada. A total of 16 random samples of 50 patients per month for 8 consecutive months pre-intervention (October 2017 to May 2018) and 8 months post intervention (January 2019 to August 2019) were selected for a total of 800 patients. There were no exclusion criteria. INTERVENTION: The delirium program included multiple components: education of staff and hospital leadership, twice per day bed-side screen for delirium, non-pharmacological and pharmacological prevention, and intervention strategies and a delirium consultation team. MEASUREMENT: Delirium prevalence was assessed using the evidence-based delirium chart abstraction method, CHART-del. Demographic data as well as fall incidence were also collected. RESULT: Our evaluation showed that the implementation of a multicomponent delirium program led to a reduction in delirium prevalence and fall incidences. The reduction in both delirium and falls was the largest for patients in the ages between 72 and 83 years old and varied across inpatient units. CONCLUSION: A multi-component delirium program to improve the prevention, recognition, and management of delirium reduces the prevalence of delirium and fall incidence among patients in general medicine units.

Multi-center validation of Catquest-9SF visual function questionnaire in Ontario, Canada.

PURPOSE: To investigate the psychometric performance and responsiveness of Catquest-9SF, a patient-reported questionnaire developed to evaluate visual function as related to daily tasks, in patients referred for cataract surgery in Ontario, Canada. METHODS: This is a pooled analysis on prospective data collected for previous projects. Subjects were recruited from three tertiary care centers in Peel region, Hamilton, and Toronto, Ontario, Canada. Catquest-9SF was administered pre-operative and post-operatively to patients with cataract. Psychometric properties, including category threshold order, infit/outfit, precision, unidimensionality, targeting, and differential item functioning were tested using Rasch analysis with Winsteps software (v.4.4.4) for Catquest-9SF. Responsiveness of questionnaire scores to cataract surgery was assessed. RESULTS: 934 patients (mean age = 71.6, 492[52.7%] female) completed the pre- and post-operative Catquest-9SF questionnaire. Catquest-9SF had ordered response thresholds, adequate precision (person separation index = 2.01, person reliability = 0.80), and confirmed unidimensionality. The infit range was 0.75-1.29 and the outfit range was 0.74-1.51, with one item ('satisfaction with vision') misfitting (outfit value = 1.51). There was mistargeting of -1.07 in pre-operative scores and mistargeting of -2.43 in both pre- and post-operative scores, meaning that tasks were relatively easy for respondent ability. There was no adverse differential item functioning. There was a mean 1.47 logit improvement in Catquest-9SF scores after cataract surgery (p<0.001). CONCLUSION: Catquest-9SF is a psychometrically robust questionnaire for assessment of visual function in patients with cataract in Ontario, Canada. It is also responsive to clinical improvement after cataract surgery.

Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly.

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is ß, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.

Improving the Prevention, Detection, and Management of Delirium in Adult Inpatients; an Interprofessional Consultative Team Pilot Project.

Delirium is a common, often preventable fluctuating state of cognition associated with increased morbidity and mortality. This report describes the implementation of an interprofessional consultative Delirium Team formed to improve the prevention, detection, and management of delirium in a community hospital. Team members consulted refered inpatients with delirium to establish a care plan and provide recommendations for pharmacological and non-pharmacological management. The team also offered delirium-related education to unit staff, patients, and caregivers. Consultations were initially completed by the team Nurse Practitioner or Occupational Therapist, and complex patients were discussed with the team Geriatrician and Psychiatrist at rounds to optimize specialist input. Of the 160 patients managed by the team over the 8-month study period, two-thirds of referred patients did not require specialist consultation for their delirium management. Strategies most often recommended by experts for managing delirium were related to medical management, social/cognitive engagement, and functional mobility. Two-thirds of all recommendations made by the team were implemented. Barriers and facilitators to implementation and improving unit staff adherence are further described. The consultative Delirium Team is a promising model that should be further explored for managing an aging population in a capacity-limited medical system.

PROPHYLACTIC n CMT-3 ATTENUATES SEPSIS-INDUCED ACUTE KIDNEY INJURY IN ASSOCIATION WITH NLRP3 INFLAMMASOME ACTIVATION AND APOPTOSIS.

ABSTRACT: Background: The kidney is the most common extrapulmonary organ injured in sepsis. The current study examines the ability of aerosolized nanochemically modified tetracycline 3 (nCMT-3), a pleiotropic anti-inflammatory agent, to attenuate acute kidney injury (AKI) caused by intratracheal LPS. Methods: C57BL/6 mice received aerosolized intratracheal nCMT-3 (1 mg/kg) or saline, followed by intratracheal LPS (2.5 mg/kg) to induce acute lung injury-induced AKI. Tissues were harvested at 24 h. The effects of nCMT-3 and LPS on AKI were assessed by plasma/tissue levels of serum urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, and renal histology. Renal matrix metalloproteinase (MMP) level/activity, cytochrome C, Bax, Bcl-2, caspase-3, p38 mitogen-activated protein kinase activation, NLRP3, and caspase-1 were also measured. Apoptotic cells in kidney were determined by TUNEL assay. Renal levels of IL-1ß and IL-6 were measured to assess inflammation. Results: Acute lung injury-induced AKI was characterized by increased plasma blood urea nitrogen, creatinine, injury biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule 1), and histologic evidence of renal injury. Lipopolysaccharide-treated mice demonstrated renal injury with increased levels of inflammatory cytokines (IL-1ß, IL-6), active MMP-2 and MMP-9, proapoptotic proteins (cytochrome C, Bax/Bcl-2 ratio, cleaved caspase-3), apoptotic cells, inflammasome activation (NLRP3, caspase-1), and p38 signaling. Intratracheal nCMT-3 significantly attenuated all the measured markers of renal injury, inflammation, and apoptosis. Conclusions: Pretreatment with aerosolized nCMT-3 attenuates LPS-induced AKI by inhibiting renal NLRP3 inflammasome activation, renal inflammation, and apoptosis.

Validation of a novel patient satisfaction questionnaire for preoperative fasting in cataract surgery: a discrimination analysis.

OBJECTIVE: Preoperative fasting is routinely performed to prevent anaesthesia-related pulmonary aspiration. To capture patients' experiences with preoperative fasting, a 13-item questionnaire was developed and validated using Rasch analysis and shortened to 6 items. This extension study aims to assess this questionnaire's ability to discriminate between participants with a short versus long duration of fasting and early versus late day surgery. DESIGN: Single-centred cross-sectional study. PARTICIPANTS: Subjects were recruited via consecutive sampling of cataract patients on surgery day at Kensington Eye Institute in Toronto from February to December 2019. METHODS: A validated preoperative fasting questionnaire was administered. Discriminative ability was assessed by comparing responses in patients scheduled for surgery in the morning (8:00 am-12:00 pm) versus afternoon (12:00 pm-3:30 pm) and fasting for short (≤8 hours) versus long (>8 hours) duration. Diagnostic ability of the 6-item questionnaire relative to the 13-item questionnaire was assessed with receiver operating characteristics curve analysis. RESULTS: A total of 164 patients (mean age 70.8 ± 10.0 years; 57% female) were included. Total scores of patients having surgery in the morning were greater (i.e., less fasting-related burden) than in the afternoon (p = 0.04). There was no significant difference in scores between patients fasting for a short versus long duration (p > 0.05). Receiver operating characteristics curve analysis showed excellent diagnostic ability of the 6-item questionnaire relative to the 13-item version (area under the curve = 0.964). CONCLUSION: The 6-item questionnaire for fasting-related burden has excellent discriminative ability between early versus late surgery patients. The time fasting while awake may be a more relevant predictor of fasting-related burden relative to the total duration of fasting.

An Integrated Care Model to Support Adolescents With Diabetes-related Quality-of-life Concerns: An Intervention Study.

BACKGROUND: Our aim in this study was to determine whether participating in an integrated stepped care model for adolescents with type 1 diabetes (T1D) would lead to improvements in overall quality of life (QoL), diabetes-related quality of life (DRQoL) and glycated hemoglobin (A1C) levels compared with usual care. METHODS: A nonrandomized, 2-group, pre/post, delayed-intervention design was used for this study. The Mind Youth Questionnaire (MY-Q) was used to assess QoL and DRQoL. Adolescents attending the diabetes clinic using the stepped care model formed the intervention group (n=77). These adolescents completed the MY-Q, and the identified concerns were discussed and addressed with them by their care team as part of the care model. Adolescents attending a pediatric diabetes clinic on another site completed the MY-Q as a comparison group (n=39), results were not shared with their care team, and they received the standard care. RESULTS: There were 116 adolescents between 13 to 17 years of age, who completed the MY-Q on 2 occasions. Baseline data were obtained on the first occasion, and, on the second occasion, an average of 12 months later, there was a follow-up assessment. At follow-up, adolescents in the intervention group had a significantly higher overall QoL and reported significantly fewer concerns on DRQoL domains than those in the comparison group. Participation in the intervention group, however, did not lead to improvements in A1C. CONCLUSION: This study shows that implementing an integrated stepped care model within an interprofessional pediatric diabetes clinic can lead to the improvement of adolescents' overall QoL and DRQoL.

Engaging patients, families and professionals at the bedside using whiteboards.

Health-care systems around the world are striving to be patient-centered, and there is growing evidence that engaging patients and families in their care, as well as in efforts to redesign services, contributes to improved outcomes and experiences for patients and providers. This patient-oriented care movement includes efforts to improve the quality of information and communication between health-care professionals and patients as well as families and caregivers. Whiteboards have emerged as a best practice in hospitals to promote engagement and improve information and communication, yet with limited empirical evidence regarding their value to patients, families, or interprofessional teams. We introduced whiteboards on an acute medical unit at a community hospital and conducted an evaluation using a pre-post design collecting both qualitative and quantitative data. Baseline and post-implementation data were collected via qualitative interviews with patients/family and providers and using the Canadian Patient Experience Survey; focus groups were held with staff and members of the care team. Qualitative results highlighted improvements in communication between the care team and patients as well as family members. Implications for practice include attention to patient/family empowerment and safety, adherence to guidance for good communication, and support for regular training and education in the use of communication tools for members of the interprofessional team.

An observational study evaluating the impact on prostate patient outcomes and experiences when radiation therapists use a standard grading system tool to assess and document treatment-related toxicities and interventions.

BACKGROUND/PURPOSE: Men undergoing radiation therapy (RT) treatment for prostate cancer (PC) often experience acute urinary, bowel, sexual, and hormonal toxicities. Timely screening, management, and documentation of these toxicities is an integral part of clinician practice, ensuring patients receive the care they require. Various screening tools, completed by either the patient or the clinician, are available, which allow clinicians to collect and respond to these toxicity outcomes; however there is a paucity of literature regarding the effective use and timing of these tools during RT treatment. This study aims to evaluate the feasibility of conducting comprehensive toxicity screening and symptom management using a toxicity screening tool in one of the busiest RT departments in Canada. Specifically, the use of a toxicity screening tool and its effect on the quality of toxicity documentation, operational impact, and patient reported outcomes (PRO). METHODS: 90 consented patients were allocated to either the structured or non-structured arm. Patients in the structured arm were assessed weekly by radiation therapists for 13 toxicities across four domains (bladder, bowel, hormonal, and sexual), using an in-house developed structured questionnaire, known as the Grid, to complete the National Cancer Institute's Common Toxicity Criteria for Adverse Events v3 (CTCAEv3). Patients in the non-structured arm were assessed and had free text clinical documentation charted according to current department policy. The Expanded Prostate Cancer Index Composite (EPIC), a PRO tool to evaluate patient function and bother after prostate cancer treatment, was completed by all study patients on a weekly basis. Statistical analysis compared documentation completeness, EPIC scores, patient satisfaction, and operational impact between study arms, as well as evaluated optimal timing of toxicity assessments. RESULTS: Assessment of the non-structured arm for completeness revealed an inconsistent and insufficient amount of documentation for the bladder and bowel domains. As for both the sexual and hormonal domains, documentation was largely absent. There was no difference in EPIC scores and patient satisfaction scores between the structured arm and the non-structured arm. Evaluation of the timing of PROs showed significant week to week change for the bladder and bowel toxicities, but not the sexual and hormonal toxicities. Finally, the use of the Grid revealed no significant impact on daily operations, only increasing average treatment times by seven seconds, and did not create any additional workload for the oncologists. CONCLUSIONS: Use of the Grid increased documentation completeness without negatively impacting clinical flow or operations, despite the fact that PROs were not improved. Based on EPIC PRO scores, bladder and bowel toxicities should be evaluated on a weekly basis during RT treatment, while sexual and hormonal toxicities need only be evaluated monthly.

Nano-chemically Modified Tetracycline-3 (nCMT-3) Attenuates Acute Lung Injury via Blocking sTREM-1 Release and NLRP3 Inflammasome Activation.

BACKGROUND: Intratracheal (IT) lipopolysaccharide (LPS) causes severe acute lung injury (ALI) and systemic inflammation. CMT-3 has pleiotropic anti-inflammatory effects including matrix metalloproteinase (MMP) inhibition, attenuation of neutrophil (PMN) activation, and elastase release. CMT-3's poor water solubility limits its bioavailability when administered orally for treating ALI. We developed a nano-formulation of CMT-3 (nCMT-3) to test the hypothesis that the pleiotropic anti-inflammatory activities of IT nCMT-3 can attenuate LPS-induced ALI. METHODS: C57BL/6 mice were treated with aerosolized IT nCMT-3 or saline, then had IT LPS or saline administered 2 h later. Tissues were harvested at 24 h. The effects of LPS and nCMT-3 on ALI were assessed by lung histology, MMP level/activity (zymography), NLRP3 protein, and activated caspase-1 levels. Blood and bronchoalveolar lavage fluid (BALF) cell counts, PMN elastase, and soluble triggering receptor expressed on myelocytes-1 (sTREM-1) levels, TNF-α, IL-1ß, IL-6, IL-18, and BALF protein levels were also measured. RESULTS: LPS-induced ALI was characterized by histologic lung injury (PMN infiltration, alveolar thickening, edema, and consolidation) elevated proMMP-2, -9 levels and activity, increased NLRP-3 protein and activated caspase-1 levels in lung tissue. LPS-induced increases in plasma and BALF levels of sTREM-1, TNF-α, IL-1ß, IL-6, IL-18, PMN elastase and BALF protein levels demonstrate significant lung/systemic inflammation and capillary leak. nCMT-3 significantly ameliorated all of these LPS-induced inflammatory markers to control levels, and decreased the incidence of ALI. CONCLUSIONS: Pre-treatment with nCMT3 significantly attenuates LPS-induced lung injury/inflammation by multiple mechanisms including: MMP activation, PMN elastase, sTREM-1 release, and NLRP3 inflammasome/caspase-1 activation.

The Impact of Real-World Alternative Dosing Strategies of Palbociclib on Progression-Free Survival in Patients with Metastatic Breast Cancer.

BACKGROUND: Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, in combination with letrozole or fulvestrant has been demonstrated to prolong the progression-free survival (PFS) in patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) metastatic breast cancer. In efforts to mitigate neutropenic toxicities, oncologists in real-world practice have prescribed alternative dosing strategies with palbociclib, yet the implication on PFS is unknown. METHODS: We conducted a retrospective, observational chart review of all female patients at our clinics with HR+, HER2- metastatic breast cancer receiving palbociclib in combination with either letrozole or fulvestrant with a first dose initiated between June 2016 and December 2018 and followed their disease course until 30 April 2020. RESULTS: The median PFS for all clinic patients receiving palbociclib and letrozole (n = 63) was 40.8 months (95% confidence interval (CI) 25.6-not estimable) and 16.97 months (95% CI 8.57-not estimable) for patients receiving palbociclib and fulvestrant (n = 11). We identified seven alternative dosing strategies prescribed by oncologists, the most prevalent being prescribing palbociclib for three weeks on and two weeks off (n = 8). The Kaplan-Meier curves for PFS in patients receiving letrozole and palbociclib prescribed alternative dosing strategies appear to diverge from monograph dosing early in the treatment. Many patients prescribed palbociclib using alternative dosing strategies continued to be observed even by the 18-month timepoint. The prevalence of grade 4 neutropenia was lower for patients on palbociclib with letrozole, suggesting a possible mitigation of severe neutropenia with alternative dosing strategies. CONCLUSIONS: We conclude that alternative dosing strategies used by oncologists such as prescribing palbociclib for three weeks on, two weeks off may achieve comparable disease control while mitigating neutropenic toxicities when compared to standard monograph dosing recommendations, prolonging treatment tolerability and adherence. Further large-scale studies are needed to confirm these results for future clinical adoption.

Effects of Confounding Bias in Coronavirus Disease 2019 (COVID-19) and Influenza Vaccine Effectiveness Test-Negative Designs Due to Correlated Influenza and COVID-19 Vaccination Behaviors.

BACKGROUND: The test-negative design is commonly used to estimate influenza and coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE). In these studies, correlated COVID-19 and influenza vaccine behaviors may introduce a confounding bias where controls are included with the other vaccine-preventable acute respiratory illness (ARI). We quantified the impact of this bias on VE estimates in studies where this bias is not addressed. METHODS: We simulated study populations under varying vaccination probabilities, COVID-19 VE, influenza VE, and proportions of controls included with the other vaccine-preventable ARI. Mean bias was calculated as the difference between estimated and true VE. Absolute mean bias in VE estimates was classified as low (<10%), moderate (10% to <20%), and high (≥20%). RESULTS: Where vaccination probabilities are positively correlated, COVID-19 and influenza VE test-negative studies with influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ARI controls, respectively, underestimate VE. For COVID-19 VE studies, mean bias was low for all scenarios where influenza represented ≤25% of controls. For influenza VE studies, mean bias was low for all scenarios where SARS-CoV-2 represented ≤10% of controls. Although bias was driven by the conditional probability of vaccination, low VE of the vaccine of interest and high VE of the confounding vaccine increase its magnitude. CONCLUSIONS: Where a low percentage of controls is included with the other vaccine-preventable ARI, bias in COVID-19 and influenza VE estimates is low. However, influenza VE estimates are likely more susceptible to bias. Researchers should consider potential bias and its implications in their respective study settings to make informed methodological decisions in test-negative VE studies.

Rapid refeeding in anorexia nervosa: A dialectic balance.

OBJECTIVE: To examine the impact of our new rapid refeeding protocol on patients with anorexia nervosa (AN) in our Eating Disorders Program. We hypothesize that the new protocol would lead to a more rapid weight gain and a shorter length of stay, with no effect on medical complications or program completion. METHOD: This cohort design included consecutive inpatients and day hospital patients admitted to the program with a BMI <18 kg/m2 and a diagnosis of AN between 2007 and 2020; N = 326 patients. Main outcomes measured were rate of weight gain and length of stay. Safety indicators included electrolyte disturbances and supplementation required, complications including refeeding syndrome and completion of the program. A p value <.05 was considered statistically significant. RESULTS: Total length of stay was 21 days shorter for patients on the rapid refeeding protocol compared to the traditional refeeding protocol. Patients on the new protocol gained 0.21 more kg/week compared to patients on the old protocol. There was no difference in completion rates between programs. Electrolyte imbalances were mild to moderate and easily treated with oral electrolyte supplementation. There were no deaths or cases of refeeding syndrome with either protocol. DISCUSSION: This is the first Canadian study to assess the effectiveness and safety of rapid refeeding in an adult population. Rapid refeeding protocols can be safely administered and are cost effective. Shorter hospital admissions are desirable to minimize possible regression and dependency on inpatient services and positively impacts patients' quality of life. PUBLIC SIGNIFICANCE: This study advances the idea that rapid refeeding in patients with anorexia nervosa can be administered safely and effectively with close medical monitoring. In addition, rapid refeeding leads to shorter hospital stays, with a cost-savings to the health system. Shorter admissions are desirable to minimize possible regression and dependency on inpatient services and also positively impacts patients' quality of life.

A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response.

Flavivirus infection of cells induces massive rearrangements of the endoplasmic reticulum (ER) membrane to form viral replication organelles (ROs) which segregates viral RNA replication intermediates from the cytoplasmic RNA sensors. Among other viral nonstructural (NS) proteins, available evidence suggests for a prominent role of NS4B, an ER membrane protein with multiple transmembrane domains, in the formation of ROs and the evasion of the innate immune response. We previously reported a benzodiazepine compound, BDAA, which specifically inhibited yellow fever virus (YFV) replication in cultured cells and in vivo in hamsters, with resistant mutation mapped to P219 of NS4B protein. In the following mechanistic studies, we found that BDAA specifically enhances YFV induced inflammatory cytokine response in association with the induction of dramatic structural alteration of ROs and exposure of double-stranded RNA (dsRNA) in virus-infected cells. Interestingly, the BDAA-enhanced cytokine response in YFV-infected cells is attenuated in RIG-I or MAD5 knockout cells and completely abolished in MAVS knockout cells. However, BDAA inhibited YFV replication at a similar extent in the parent cells and cells deficient of RIG-I, MDA5 or MAVS. These results thus provided multiple lines of biological evidence to support a model that BDAA interaction with NS4B may impair the integrity of YFV ROs, which not only inhibits viral RNA replication, but also promotes the release of viral RNA from ROs, which consequentially activates RIG-I and MDA5. Although the innate immune enhancement activity of BDAA is not required for its antiviral activity in cultured cells, its dual antiviral mechanism is unique among all the reported antiviral agents thus far and warrants further investigation in animal models in future.