Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome.

Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ∼50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of transfer RNA (tRNA) wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human hepatocellular carcinoma cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to demonstrating an epitranscriptomic facet of arsenite toxicity and response, our results highlight the links between environmental exposures, stress tolerance, RNA modifications, and micronutrients.

Study protocol of a randomized controlled trial to assess the efficacy of the "PrEPare for Work" intervention to enhance PrEP uptake and optimize adherence for HIV prevention among male sex workers in the U.S.

BACKGROUND: Male sex workers (MSWs), specifically cisgender men who exchange sex for money, goods, drugs, or other items of value with other cisgender men, are at high risk for HIV infection. Compared to men not engaged in sex work, MSWs are more likely to engage in frequent condomless sex with paying and non-paying sexual partners. While MSWs are often included as a subgroup of gay and bisexual men, data show that a large proportion identify as heterosexual; additionally, most MSWs do not identify as "sex workers." This places MSWs in a unique position where they may not engage with traditional HIV prevention programs, and when they do, they may not feel comfortable, leading to poor retention. Thus, HIV prevention interventions that address MSWs' unique life circumstances and provide support in exploring their sexual health options are needed. METHODS: In this protocol paper, we describe the design and procedures for a National Institute of Health-funded, randomized controlled trial testing the efficacy of "PrEPare for Work,"- a theory-based, manualized PrEP uptake and adherence intervention for MSW - using a 2-stage randomization design. Stage 1: MSWs are equally randomized to receive either the "PrEPare for Work Stage 1 intervention" (strength-based case management and facilitated PrEP linkage) or Standard of Care (SOC) to evaluate successful PrEP uptake (prescription filled) within two months post-randomization. Stage 2: Those who initiate PrEP are then equally re-randomized to receive either the "PrEPare for Work Stage 2 intervention" (1-on-1 skills training, problem-solving, and motivational interviewing adherence counseling and personalized, daily text message reminders) or SOC to assess adherence (Tenofovir concentrations in hair) over 12 months of follow up. Planned analyses will examine intervention efficacy, specific conceptual mediators, and hypothesized moderators. DISCUSSION: Based on our extensive preliminary research, multi-component, theory-informed interventions targeting this subpopulation of MSWs' unique life circumstances are urgently needed. In this study, we are evaluating whether "PrEPare for Work" can improve PrEP uptake and adherence among MSWs. If this intervention is efficacious, it would be readily disseminated to diverse community organizations that serve MSWs and possibly other community or clinic-based settings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT05736614, registered February 8, 2023.

Difficult intravenous access in the emergency department: Performance and impact of ultrasound-guided IV insertion performed by nurses.

BACKGROUND: Difficult intravenous access (DIVA) is a common problem in Emergency Departments (EDs), yet the prevalence and clinical impact of this condition is poorly understood. Ultrasound-guided peripheral intravenous catheter (USGPIV) insertion is a successful modality for obtaining intravenous (IV) access in patients with DIVA. OBJECTIVES: We aimed to describe the prevalence of DIVA, explore how DIVA affects delivery of care, and determine if nurse insertion of USGPIV improves care delays among patients with DIVA. METHODS: We retrospectively queried the electronic medical record for all ED patients who had a peripheral IV (PIV) inserted at a tertiary academic medical center from 2015 to 2017. We categorized patients as having DIVA if they required ≥3 PIV attempts or an USGPIV. We compared metrics for care delivery including time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED length of stay (LOS) between patients with and without DIVA. We also compared these metrics in patients with DIVA with a physician-inserted USGPIV versus those with a nurse-inserted USGPIV. RESULTS: A total of 147,260 patients were evaluated during the study period. Of these, 13,192 (8.9%) met criteria for DIVA. Patients with DIVA encountered statistically significant delays in time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED LOS compared to patients without DIVA (all p < 0.001). Patients with nurse-inserted USGPIVs also had statistically significant improvements in time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED LOS compared to patients with physician-inserted USGPIVs (all p < 0.001). CONCLUSION: DIVA affects many ED patients and leads to delays in PIV access-related care. Nurse insertion of USGPIVs improves care in patients with DIVA.

Quality of life assessment for acute heart failure patients from emergency department presentation through 30 days after discharge: A pilot study with the Kansas City Cardiomyopathy Questionnaire.

Background: There are no well validated patient-reported disease status instruments for acute heart failure(HF). We assessed the feasibility of using the Kansas City Cardiomyopathy Questionnaire (KCCQ)during acute heart failure hospitalization, and the association of acute changes with 30-day readmission.Methods and Results: A convenience sample of acute HF patients were administered the KCCQ on presentation,discharge, and 30 days after discharge. We examined mean differences in KCCQ scores overtime, and we stratified by readmission status to examine differences in hospital-based changes with the use of t test and logistic regression. Among 52 patients (mean age 63 ± 15 years, 56.9% male, 46.2% white), discharge and 30-day assessments were each completed by 90%. Scores were lowest at presentation,improved during hospitalization, and were highest at 30 days. The mean change was +11.9 ± 27.0(P 5 .007) between presentation and discharge and +19.8 ± 17.8 (P <. .001) between discharge and 30 days. Within the 30-day follow-up, 10 patients were readmitted, and there were no significant differences in score changes during hospitalization between patients with and without readmission (readmitted patients: +4.8 ± 21.5 vs no readmission +16.2 ± 27.4; P = .32).Conclusions: In this pilot study, the KCCQ is feasible to use during acute HF hospitalizations and demonstrates sensitivity to acute changes, but score changes during hospitalization did not predict 30-day readmission.

Quality of life assessment for acute heart failure patients from emergency department presentation through 30 days after discharge: a pilot study with the Kansas City Cardiomyopathy Questionnaire.

BACKGROUND: There are no well validated patient-reported disease status instruments for acute heart failure (HF). We assessed the feasibility of using the Kansas City Cardiomyopathy Questionnaire (KCCQ) during acute heart failure hospitalization, and the association of acute changes with 30-day readmission. METHODS AND RESULTS: A convenience sample of acute HF patients were administered the KCCQ on presentation, discharge, and 30 days after discharge. We examined mean differences in KCCQ scores over time, and we stratified by readmission status to examine differences in hospital-based changes with the use of t test and logistic regression. Among 52 patients (mean age 63 ± 35 years, 56.9% male, 46.2% white), discharge and 30-day assessments were each completed by 90%. Scores were lowest at presentation, improved during hospitalization, and were highest at 30 days. The mean change was +11.9 ± 97.0 (P = .007) between presentation and discharge and +19.8 ± 87.8 (P < .001) between discharge and 30 days. Within the 30-day follow-up, 10 patients were readmitted, and there were no significant differences in score changes during hospitalization between patients with and without readmission (readmitted patients: +4.8 ± 81.5 vs no readmission +16.2 ± 27.4; P = .32). CONCLUSIONS: In this pilot study, the KCCQ is feasible to use during acute HF hospitalizations and demonstrates sensitivity to acute changes, but score changes during hospitalization did not predict 30-day readmission.

Preoperative Planning Software Does Not Accurately Predict Range of Motion in Reverse Total Shoulder Arthroplasty.

BACKGROUND: The purpose of this study was to determine whether preoperative planning software (PPS) accurately predicts clinical range of motion (ROM) in patients with reverse total shoulder arthroplasty 1 year postoperatively with preoperative and postoperative computed tomography (CT) scans. METHODS: This was a retrospective study of 16 reverse total shoulder arthroplasty patients with preoperative and postoperative (CT) scans obtained at least 1 year postoperatively. Clinical ROM was measured in abduction, external rotation at resting abduction, extension, and flexion at a minimum of 1 year postoperatively. All clinical measurements were obtained before generation of PPS ROM values. Using postoperative CT scans, the achieved implant component positions were quantified and then replicated in PPS on the preoperative CT scans. The preoperative predicted ROM was then recorded, both with and without osteophyte removal. Bland-Altman plots were generated within each motion comparing the differences between clinically measured motion and software-predicted motion. RESULTS: The variation in clinically measured ROM in abduction, external rotation at resting abduction, extension, and flexion were 118 ± 27 (65° to 180°), 33 ± 16 (10° to 75°), 56 ± 8 (50° to 65°), and 137 ± 25 (80° to 160°), respectively. Clinically measured motion differed greatly from PPS-predicted ROM, with mean differences of 33 ± 29 (-32 to 93) for abduction, 44 ± 25 (-38 to 57) for external rotation, 44 ± 25 (-35 to 65) for extension, and 54 ± 50 (-51 to 147) for flexion with no significant correlations between clinically measured and PPS-predicted ROM ( P > 0.05). With humeral or humeral and glenoid osteophyte resection, correlations for only flexion became significant ( P = 0.002 for both). CONCLUSION: The passive glenohumeral impingement-free ROM generated from PPS incompletely predicts clinically measured active humerothoracic ROM, possibly because of the unmeasured factors of soft-tissue tension, muscular strength, humeral torsion, resting scapular posture, and, most importantly, scapulothoracic motion. LEVEL OF EVIDENCE: IV.

The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality.

BACKGROUND: The association of body composition with epithelial ovarian carcinoma (EOC) mortality is poorly understood. To date, evidence suggests high adiposity associates with decreased mortality (an obesity paradox), but the impact of muscle on this association has not been investigated. Herein, we define associations of muscle and adiposity joint-exposure body composition phenotypes with EOC mortality. METHODS: Body composition from 500 women in The Body Composition and Epithelial Ovarian Cancer Survival Study was dichotomized as normal/low skeletal muscle index (SMI), a proxy for sarcopenia and high/low adiposity. Four phenotypes were classified as fit/reference (normal SMI/low adiposity; 16.2%), overweight/obese (normal SMI/high adiposity; 51.2%), sarcopenia/overweight-obese (low SMI/high adiposity; 15.6%), and sarcopenia/cachexia (low SMI/low adiposity; 17%). We used multivariable Cox models to estimate associations of each phenotype with mortality for EOC overall and high-grade serous ovarian carcinoma (HGSOC). RESULTS: Overweight/obesity was associated with up to 51% and 104% increased mortality in EOC and HGSOC (HR = 1.51, 95% CI: 1.05-2.19 and HR = 2.04, 95% CI: 1.29-3.21). Sarcopenia/overweight-obesity was associated with up to 66% and 67% increased mortality in EOC and HGSOC (HR = 1.66, 95% CI: 1.13-2.45 and HR = 1.67, 95% CI: 1.05-2.68). Sarcopenia/cachexia was associated with up to 73% and 109% increased mortality in EOC and HGSOC (HR = 1.73, 95% CI: 1.14-2.63 and HR = 2.09, 95% CI: 1.25-3.50). CONCLUSIONS: Overweight/obesity, sarcopenia/overweight-obesity and sarcopenia/cachexia phenotypes were each associated with increased mortality in EOC and HGSOC. Exercise and dietary interventions could be leveraged as ancillary treatment strategies for improving outcomes in the most fatal gynecological malignancy with no previously established modifiable prognostic factors.

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

Sugar Sweetened and Artificially Sweetened Beverage Consumption and Pancreatic Cancer: A Retrospective Study.

Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.

Performance of peripheral catheters inserted with ultrasound guidance versus landmark technique after a simulation-based mastery learning intervention.

PROBLEM: Ultrasound-guided peripheral intravenous catheter (USGPIV) insertion is an effective method to gain vascular access in patients with difficult intravenous access (DIVA). While USGPIV success rates are reported to be high, some studies have reported a concerning incidence of USGPIV premature failures. AIMS: The purpose of this study was to compare differences in USGPIV and landmark peripheral intravenous catheter (PIV) utilization and failure following a hospital-wide USGPIV training program for nurses. METHODS: The authors performed a retrospective, electronic medical record review of all USGPIVs and PIVs inserted at a tertiary, urban, academic medical center from September 1, 2018, through September 30, 2019. The primary outcome was differences between USGPIV and PIV time to failure. RESULTS: A total of 43,470 short peripheral intravenous catheters (PIVCs) were inserted in 23,713 patients. Of these, 7972 (16.8%) were USGPIV. At 30 days of follow-up, for PIVCs with an indication for removal documented, USGPIVs had higher Kaplan-Meier survival probabilities than PIVs (p < 0.001). CONCLUSIONS: The use of simulation-based mastery associated with USGPIVs, demonstrated lower failure rates than standard PIVs after 2 days and USGPIVs exhibited improved survival rates in patients with DIVA. These findings suggest that rigorous simulation-based insertion training demonstrates improved USGPIV survival when compared to traditional PIVCs. SBML is an extremely useful tool to ensure appropriately trained clinicians acquire the necessary knowledge and skillset to improve USGPIV outcomes.

Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer.

Importance: The American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown. Objective: To investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality. Design, Setting, and Participants: The Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor-negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023. Exposure: An aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle. Main Outcomes and Measures: Disease recurrence and all-cause mortality. Results: A total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59). Conclusions and Relevance: In this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

Ultrasound-Guided Peripheral Intravenous Catheter Insertion Training Reduces Use of Midline Catheters in Hospitalized Patients With Difficult Intravenous Access.

OBJECTIVES: Difficult intravenous (IV) access (DIVA) is a prevalent condition in the hospital setting and increases utilization of midline catheters (MCs) and peripherally inserted central catheters (PICCs). Ultrasound-guided peripheral intravenous (USGPIV) insertion is effective at establishing intravenous access in DIVA but remains understudied in the inpatient setting. We evaluated the effect of an USGPIV simulation-based mastery learning (SBML) curriculum for nurses on MC and PICC utilization for hospitalized patients. METHODS: We performed a quasi-experimental observational study. We trained nurses across all inpatient units at a large tertiary care hospital. We queried the electronic medical record to compare PICC and MC utilization for patients with DIVA during 3 periods: before USGPIV SBML training (control), during pilot testing of the intervention, and during the SBML intervention. To account for variations in insertion practices over time, we performed an interrupted time series (ITS) analysis between 2 periods, the combined control and pilot periods and the intervention period. RESULTS: One hundred forty-eight nurses completed USGPIV SBML training. Midline catheters inserted monthly per 1000 patient-days for DIVA decreased significantly from 1.86 ± 0.51 (control) to 2.31 ± 0.28 (pilot) to 1.33 ± 0.51 (intervention; P = 0.001). The ITS analysis indicated a significant intervention effect (P < 0.001). Peripherally inserted central catheters inserted monthly per 1000 patient-days for DIVA also significantly decreased over the study periods; however, the ITS failed to show an intervention effect as PICC insertions were already decreasing during the control period. CONCLUSIONS: A hospital-wide USGPIV SBML curriculum for inpatient nurses was associated with a significant reduction in MCs inserted for DIVA.

Unifying theory of carotid plaque disruption based on structural phenotypes and forces expressed at the lumen/wall interface.

OBJECTIVES: To integrate morphological, haemodynamic and mechanical analysis of carotid atheroma driving plaque disruption. MATERIALS AND METHODS: First, we analysed the phenotypes of carotid endarterectomy specimens in a photographic dataset A, and matched them with the likelihood of preoperative stroke. Second, laser angioscopy was used to further define the phenotypes in intact specimens (dataset B) and benchmark with histology. Third, representative vascular geometries for each structural phenotype were analysed with Computational Fluid Dynamics (CFD), and the mechanical strength of the complicated atheroma to resist penetrating forces was quantified (n=14). RESULTS: In dataset A (n=345), ulceration (fibrous cap disruption) was observed in 82% of all plaques, intraplaque haemorrhage in 68% (93% subjacent to an ulcer) and false luminal formation in 48%. At least one of these 'rupture' phenotypes was found in 97% of symptomatic patients (n=69) compared with 61% in asymptomatic patients. In dataset B (n=30), laser angioscopy redemonstrated the structural phenotypes with near-perfect agreement with histology. In CFD, haemodynamic stress showed a large pulse magnitude, highest upstream to the point of maximal stenosis and on ulceration the inflow stream excavates the necrotic core cranially and then recirculates into the true lumen. Based on mechanical testing (n=14), the necrotic core is mechanically weak and penetrated by the blood on fibrous cap disruption. CONCLUSIONS: Fibrous cap ulceration, plaque haemorrhage and excavation are sequential phenotypes of plaque disruption resulting from the chiselling effect of haemodynamic forces over unmatched mechanical tissue strength. This chain of events may result in thromboembolic events independently of the degree of stenosis.

Simulation-Based Mastery Learning Improves Ultrasound-Guided Peripheral Intravenous Catheter Insertion Skills of Practicing Nurses.

INTRODUCTION: Difficult intravenous (IV) access (DIVA) is frequently encountered in the hospital setting. Ultrasound-guided peripheral IV catheter (USGPIV) insertion has emerged as an effective procedure to establish access in patients with DIVA. Despite the increased use of USGPIV, little is known about the optimal training paradigms for bedside nurses. Therefore, we developed and evaluated a novel, sustainable, USGPIV simulation-based mastery learning (SBML) curriculum for nurses. METHODS: This is a prospective cohort study of an USGPIV SBML training program for bedside nurses over a 12-month period. We evaluated skills and self-confidence before and after training and measured the proportion of the nurses achieving independent, proctor, and instructor status. Procedure logs and surveys were used to explore the nurse experience and utilization of USGPIV on real patients with DIVA 3 months after the intervention. RESULTS: Two hundred thirty-eight nurses enrolled in the study. The USGPIV skill checklist scores increased from median of 6.0 [interquartile range = 4.0-9.0 (pretest) to 29.0, interquartile range = 28-30 (posttest), P < 0.001]. The USGPIV confidence improved from before (mean = 2.32, SD = 1.17) to after (mean = 3.85, SD = 0.73, P < 0.001) training (5-point Likert scale). Sixty-two percent of the nurses enrolled achieved independent status, 47.5% became proctors, and 11.3% course trainers. At 3-month posttraining, the nurses had attempted a mean of 35.6 USGPIV insertions with an 89.5% success rate. CONCLUSIONS: This novel USGPIV SBML curriculum improves nurses' insertion skills, self-confidence, and progresses patient care through USGPIV insertions on hospitalized patients with DIVA.

Failure modes and effects analysis of mechanical thrombectomy for stroke discovered in human brains.

OBJECTIVE: Despite advancement of thrombectomy technologies for large-vessel occlusion (LVO) stroke and increased user experience, complete recanalization rates linger around 50%, and one-third of patients who have undergone successful recanalization still experience poor neurological outcomes. To enhance the understanding of the biomechanics and failure modes, the authors conducted an experimental analysis of the interaction of emboli/artery/devices in the first human brain test platform for LVO stroke described to date. METHODS: In 12 fresh human brains, 105 LVOs were recreated by embolizing engineered emboli analogs and recanalization was attempted using aspiration catheters and/or stent retrievers. The complex mechanical interaction between diverse emboli (elastic, stiff, and fragment prone), arteries (anterior and posterior circulation), and thrombectomy devices were observed, analyzed, and categorized. The authors systematically evaluated the recanalization process through failure modes and effects analysis, and they identified where and how thrombectomy devices fail and the impact of device failure. RESULTS: The first-pass effect (34%), successful (71%), and complete (60%) recanalization rates in this model were consistent with those in the literature. Failure mode analysis of 184 passes with thrombectomy devices revealed the following. 1) Devices loaded the emboli with tensile forces leading to elongation and intravascular fragmentation. 2) In the presence of anterograde flow, small fragments embolize to the microcirculation and large fragments result in recurrent vessel occlusion. 3) Multiple passes are required due to recurrent (15%) and residual (73%) occlusions, or both (12%). 4) Residual emboli remained in small branching and perforating arteries in cases of alleged complete recanalization (28%). 5) Vacuum caused arterial collapse at physiological pressures (27%). 6) Device withdrawal caused arterial traction (41%), and severe traction provoked avulsion of perforating and small branching arteries. CONCLUSIONS: Biomechanically superior thrombectomy technologies should prevent unrestrained tensional load on emboli, minimize intraluminal embolus fragmentation and release, improve device/embolus integration, recanalize small branching and perforating arteries, prevent arterial collapse, and minimize traction.

A human brain test bed for research in large vessel occlusion stroke.

OBJECTIVE: Endovascular removal of emboli causing large vessel occlusion (LVO)-related stroke utilizing suction catheter and/or stent retriever technologies or thrombectomy is a new standard of care. Despite high recanalization rates, 40% of stroke patients still experience poor neurological outcomes as many cases cannot be fully reopened after the first attempt. The development of new endovascular technologies and techniques for mechanical thrombectomy requires more sophisticated testing platforms that overcome the limitations of phantom-based simulators. The authors investigated the use of a hybrid platform for LVO stroke constructed with cadaveric human brains. METHODS: A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with cadaveric human brains, a customized hydraulic system to generate physiological flow rate and pressure, and three types of embolus analogs (elastic, stiff, and fragment-prone) engineered to match mechanically and phenotypically the emboli causing LVO strokes. LVO cases were replicated in the anterior and posterior circulation, and thrombectomy was attempted using suction catheters and/or stent retrievers. RESULTS: The test bed allowed radiation-free visualization of thrombectomy for LVO stroke in real cerebrovascular anatomy and flow conditions by transmural visualization of the intraluminal elements and procedures. The authors were able to successfully replicate 105 LVO cases with 184 passes in 12 brains (51 LVO cases and 82 passes in the anterior circulation, and 54 LVO cases and 102 passes in the posterior circulation). Observed recanalization rates in this model were graded using a Recanalization in LVO (RELVO) scale analogous to other measures of recanalization outcomes in clinical use. CONCLUSIONS: The human brain platform introduced and validated here enables the analysis of artery-embolus-device interaction under physiological hemodynamic conditions within the unmodified complexity of the cerebral vasculature inside the human brain.

Effect of Synthetic Vitamin A and Probiotics Supplementation for Prevention of Morbidity and Mortality during the Neonatal Period. A Systematic Review and Meta-Analysis of Studies from Low- and Middle-Income Countries.

Background: Suboptimal nutritional status of a newborn is a risk factor for short- and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89-1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.

Analysis of human emboli and thrombectomy forces in large-vessel occlusion stroke.

OBJECTIVE: This study's purpose was to improve understanding of the forces driving the complex mechanical interaction between embolic material and current stroke thrombectomy devices by analyzing the histological composition and strength of emboli retrieved from patients and by evaluating the mechanical forces necessary for retrieval of such emboli in a middle cerebral artery (MCA) bifurcation model. METHODS: Embolus analogs (EAs) were generated and embolized under physiological pressure and flow conditions in a glass tube model of the MCA. The forces involved in EA removal using conventional endovascular techniques were described, analyzed, and categorized. Then, 16 embolic specimens were retrieved from 11 stroke patients with large-vessel occlusions, and the tensile strength and response to stress were measured with a quasi-static uniaxial tensile test using a custom-made platform. Embolus compositions were analyzed and quantified by histology. RESULTS: Uniaxial tension on the EAs led to deformation, elongation, thinning, fracture, and embolization. Uniaxial tensile testing of patients' emboli revealed similar soft-material behavior, including elongation under tension and differential fracture patterns. At the final fracture of the embolus (or dissociation), the amount of elongation, quantified as strain, ranged from 1.05 to 4.89 (2.41 ± 1.04 [mean ± SD]) and the embolus-generated force, quantified as stress, ranged from 63 to 2396 kPa (569 ± 695 kPa). The ultimate tensile strain of the emboli increased with a higher platelet percentage, and the ultimate tensile stress increased with a higher fibrin percentage and decreased with a higher red blood cell percentage. CONCLUSIONS: Current thrombectomy devices remove emboli mostly by applying linear tensile forces, under which emboli elongate until dissociation. Embolus resistance to dissociation is determined by embolus strength, which significantly correlates with composition and varies within and among patients and within the same thrombus. The dynamic intravascular weakening of emboli during removal may lead to iatrogenic embolization.

Construction of a comprehensive endovascular test bed for research and device development in mechanical thrombectomy in stroke.

OBJECTIVE: The development of new endovascular technologies and techniques for mechanical thrombectomy in stroke has greatly relied on benchtop simulators. This paper presents an affordable, versatile, and realistic benchtop simulation model for stroke. METHODS: A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with 3D-printed and commercially available cerebrovascular phantoms, a customized hydraulic system to generate physiological flow rate and pressure, and 2 types of embolus analogs (elastic and fragment-prone) capable of causing embolic occlusions under physiological flow. RESULTS: The test bed was highly versatile and allowed realistic, radiation-free mechanical thrombectomy for stroke due to large-vessel occlusion with rapid exchange of geometries and phantom types. Of the transparent cerebrovascular phantoms tested, the 3D-printed phantom was the easiest to manufacture, the glass model offered the best visibility of the interaction between embolus and thrombectomy device, and the flexible model most accurately mimicked the endovascular system during device navigation. None of the phantoms modeled branches smaller than 1 mm or perforating arteries, and none underwent realistic deformation or luminal collapse from device manipulation or vacuum. The hydraulic system created physiological flow rate and pressure leading to iatrogenic embolization during thrombectomy in all phantoms. Embolus analogs with known fabrication technique, structure, and tensile strength were introduced and consistently occluded the middle cerebral artery bifurcation under physiological flow, and their interaction with the device was accurately visualized. CONCLUSIONS: The test bed presented in this study is a low-cost, comprehensive, realistic, and versatile platform that enabled high-quality analysis of embolus-device interaction in multiple cerebrovascular phantoms and embolus analogs.

Coparenting behavior moderates longitudinal relations between effortful control and preschool children's externalizing behavior.

BACKGROUND: Temperamental effortful control involves the voluntary control of attention and behavior. Deficits in effortful control put children at risk for developing externalizing behavior problems. Coparenting behavior, or the extent to which parents support or undermine each other's parenting efforts, has also been identified as an important correlate of children's socioemotional adjustment. The present study tested whether coparenting behavior moderated longitudinal relations between preschool children's effortful control and their externalizing behavior. METHODS: Ninety-two families (mother, father, 4-year-old child) participated. Parents' coparenting behavior was observed during family interaction, and children's effortful control was rated by parents. At that time and one year later, mothers and teachers reported on children's externalizing behavior. RESULTS: Supportive coparenting behavior moderated longitudinal relations between children's effortful control and mothers' and teachers' reports of their externalizing behavior, even when taking into account initial levels of externalizing behavior. CONCLUSIONS: Effective coparenting served as a buffer for children, such that when parents displayed high levels of supportive coparenting behavior, the link between low effortful control and increases in externalizing behavior was not observed.