Capillary density and caliber as assessed by optical coherence tomography angiography may be significant predictors of diabetic retinopathy severity.

PURPOSE: To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. METHODS: This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. RESULTS: This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. CONCLUSION: OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.

A retrospective data analysis on the induction medications used in trauma rapid sequence intubations and their effects on outcomes.

PURPOSE: Rapid sequence intubation (RSI) in trauma patients is common; however, the induction agents used have been debated. We determined which induction medications were used most frequently for adult trauma RSIs and their associations with hemodynamics and outcomes. We hypothesized that etomidate is the most commonly used induction agent and has similar outcomes to other induction agents. METHODS: This retrospective review at two U.S. level I trauma centers evaluated adult trauma patients undergoing RSI within 24 h of admission, between 01/01/2016 and 12/31/2017. We compared patient characteristics and outcomes by induction agent. Comparisons on the primary outcome of in-hospital mortality and secondary outcomes of peri-intubation hypotension, hospital and ICU length of stay (LOS), ventilator days, and complications used logistic regression or negative binomial regression. Regression models adjusted for hospital site, age, patient severity measures, and intubation location. RESULTS: Among 1303 trauma patients undergoing RSI within 24 h of admission, 948 (73%) were intubated in the emergency department (ED) and 325 (25%) in the operating room (OR). The most common induction agents were etomidate (68%), propofol (17%), and ketamine (11%). In-hospital mortality was highest in the etomidate group (25.5%), followed by ketamine (17%), and propofol (1.8%). CONCLUSION: Etomidate was most commonly used in ED intubations; propofol was most used in the OR. Compared to propofol, patients induced with etomidate had higher mortality and complication rates. Findings should be interpreted with caution given limited generalizability and residual confounding by indication.

Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women.

OBJECTIVES: To compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology and total cancer incidence among healthy postmenopausal women. STUDY DESIGN: This study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17-beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo. MAIN OUTCOME MEASURES: Participants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence. RESULTS: Over up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated. CONCLUSION: Our results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women. ClinicalTrials.gov registration NCT00114517.

Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series.

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Network meta-analysis of drug-coated balloon angioplasty versus primary nitinol stenting for femoropopliteal atherosclerotic disease.

OBJECTIVE: Primary nitinol stenting (PNS) and drug-coated balloon (DCB) angioplasty are two of the most common endovascular interventions for femoropopliteal atherosclerotic disease. Although many prospective randomized controlled trials have compared PNS or DCB with plain balloon angioplasty (POBA), no studies have directly compared PNS against DCB therapy. The purpose of this network meta-analysis is to determine whether there is a significant difference in outcomes between PNS and DCB. METHODS: The primary outcome measure was binary restenosis, the secondary outcome measures were target lesion revascularization (TLR) and change in the ankle-brachial index (ABI). Outcomes were evaluated at 6, 12, and 24 months. A literature review identified all randomized controlled trials published before March 2020 that compared DCB with POBA or PNS with POBA in the treatment of native atherosclerotic lesions of the femoropopliteal artery. Studies were excluded if they contained in-stent stenosis or tibial artery disease that could not be delineated out in a subgroup analysis. Network meta-analysis was performed using the network and mvmeta commands in STATA 14. RESULTS: Twenty-seven publications covering 19 trials were identified; 8 trials compared PNS with POBA and 11 trials compared DCB with POBA. The odds of freedom from binary restenosis for patients treated with DCB compared with PNS at 6 months was 1.19 (95% confidence interval [CI], 0.63-2.22), at 12 months was 1.67 (95% CI, 1.04-2.68), and at 24 months was 1.36 (95% CI, 0.78-2.37). The odds of freedom from TLR for patients treated with DCB compared with PNS at 6 months was 0.66 (95% CI, 0.12-3.80), at 12 months was 1.89 (95% CI, 1.04-3.45), and at 24 months was 1.68 (95% CI, 0.82-3.44). The mean increase in ABI for patients treated with PNS compared with DCB at 6 months was 0.06 higher (95% CI, -0.03 to 0.15), at 12 months was 0.05 higher (95% CI, 0.00-0.09), and at 24 months was 0.07 higher (95% CI, -0.01 to 0.14). CONCLUSIONS: Both DCB and PNS demonstrated a lower rate of binary restenosis compared with POBA at the 6-, 12-, and 24-month timepoints. When comparing DCB with PNS through network meta-analysis, DCB had a statistically lower rate of a binary restenosis and TLR at the 12-month timepoint. This network meta-analysis demonstrates that both DCB and PNS are superior to POBA, and that PNS is a satisfactory substitute for DCB when paclitaxel is not desirable.

Feasibility of quantifying change in immune white cells in abdominal adipose tissue in response to an immune modulator in clinical obesity.

BACKGROUND: Obesity is often associated with inflammation in adipose tissue (AT) with release of mediators of atherogenesis. We postulated that it would be feasible to collect sufficient abdominal AT to quantify changes in a broad array of adaptive and innate mononuclear white cells in obese non-diabetic adults in response to a dipeptidyl protease inhibitor (DPP4i), known to inhibit activation of immune white cells. METHODS: Adults 18-55 years-of-age were screened for abdominal obesity and insulin resistance or impaired glucose tolerance but without known inflammatory conditions. Twenty-one eligible participants consented for study and were randomized 3:1 to receive sitagliptin (DPP4i) at 100mg or matching placebo daily for 28 days. Abdominal AT collected by percutaneous biopsy and peripheral blood mononuclear cell fractions were evaluated before and after treatment; plasma was stored for batch testing. RESULTS: Highly sensitive C-reactive protein, a global marker of inflammation, was not elevated in the study population. Innate lymphoid cells (ILC) type 3 (ILC-3) in abdominal AT decreased with active treatment compared with placebo (p = 0.04). Other immune white cells in AT and peripheral blood mononuclear cell (PBMC) fractions did not change with treatment compared to placebo (p>0.05); although ILC-2 declined in PBMCs (p = 0.007) in the sitagliptin treatment group. Two circulating biomarkers of atherogenesis, interferon-inducible protein-10 (IP-10) and sCD40L declined in plasma (p = 0.02 and p = 0.07, respectively) in the active treatment group, providing indirect validation of a net reduction in inflammation. CONCLUSIONS: In this pilot study, two cell types of the innate lymphoid system, ILC-3 in AT and ILC-2 PBMCs declined during treatment and as did circulating biomarkers of atherogenesis. Changes in other immune cells were not demonstrable. The study showed that sufficient abdominal AT could be obtained to quantify white cells of both innate and adaptive immunity and to demonstrate changes during therapy with an immune inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT number): NCT02576.

Challenges in Using Insurance Claims Data to Identify Palliative Care Patients for a Research Trial.

BACKGROUND: Little is known about strategies for enrolling patients in home-based palliative care programs despite the need to conduct effectiveness studies of this emerging industry. PURPOSE: We used medical claims data from Accountable Care Organizations in California to identify patients for a randomized controlled trial of home-based palliative care. We report outcomes from this strategy and the implications for future research. RESULTS: Claims data identified 1357 patients. Research assistants could not reach 986 patients (72.7%), usually because the phone calls went unanswered (38.5%) and many patients' phone numbers were missing or incorrect (16.3%). Of 371 patients reached, 163 opted out. Of 208 patients screened, 177 were ineligible for the trial. Just 10 patients were enrolled. RECOMMENDATIONS: Our findings suggest that medical claims data may not be useful for engaging patients potentially eligible for palliative care research trials. We recommend that alternative identification and recruitment strategies be considered.

The Predictive Capacity of American Society of Anesthesiologists Physical Status (ASA PS) Score in Burn Patients.

Advances in burn care continues to improve survival rates and patient outcomes. There are several burn prognostic tools used to predict mortality and outcomes; however, none include patient comorbidities. We used the American Society of Anesthesiologists physical status score as a surrogate measure for comorbidities, and evaluated its role in predicting mortality and outcomes in adult burn patients undergoing surgery. A retrospective analysis was performed on data collected from a single burn center in the United States, which was comprised of 183 patients. We evaluated the American Society of Anesthesiologists physical status score as an independent predictor of mortality and outcomes, including intensive care unit (ICU) length of stay (LOS), hospital LOS, mechanical ventilator (MV) days, and complications. We compared the American Society of Anesthesiologists physical status score to other prognostic models which included the revised Baux score, Belgian Outcome in Burn Injury, and the Abbreviated Burn Severity Index. Our results demonstrated that the revised Baux and American Society of Anesthesiologists physical status scores could be used to determine the mortality risk in adult burn patients. The revised Baux was the best predictor of mortality, ICU LOS, and MV days, while the Abbreviated Burn Severity Index was the best predictor of total LOS.

Discrepancy in Neurologic Outcomes Following Aneurysmal Subarachnoid Hemorrhage as a Function of Socioeconomic Class.

OBJECTIVE: To investigate potential health care discrepancies in patients with ruptured cerebral aneurysms undergoing microsurgical intervention. METHODS: We retrospectively reviewed patients with ruptured intracranial aneurysms treated at our tertiary referral university hospital (UH) and safety net county hospital (CH) from 2010 to 2015. We identified 73 UH patients and 58 CH patients. RESULTS: UH patients had shorter time duration between rupture and intervention (P < 0.001) and higher rates of intubation on admission (P = 0.01). Verapamil was more frequently used for clinical vasospasm in UH patients, at 0.13 (95% confidence interval [CI], 0.09-0.18) treatments per patient per day versus 0.077 (95% CI, 0.047-0.12) treatments per patient per day in CH patients, though there was no difference in delayed cerebral ischemia (P = 0.15). The majority of the CH cohort was uninsured (26.3%; UH 0%) or had Medicaid (59.7%; UH 35.2%) (P < 0.001). The UH had more dispositions to home or rehabilitation centers than the CH (82% vs. 67.3%; P = 0.04). After adjusting for disease severity, hospital stay, and insurance status, CH patients were 3.73 (95% CI, 1.25-12.14) times more likely to be discharged with a poor modified Rankin Scale score and 3.08 (95% CI, 1.04-9.61) times more likely to be discharged with a poor Glasgow Outcome Scale score compared with UH patients (P = 0.02 and P = 0.04, respectively). CONCLUSIONS: Limited resource availability in a safety net hospital system could be a major driving force behind the health care discrepancy identified in our ruptured cerebral aneurysm population. Reallocation of resources to supplement advanced inpatient acute care technologies and, more importantly, post-acute care environments can narrow the outcomes gap.

Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes.

BACKGROUND: Persistent Staphylococcus aureus bacteremia (SAB) is defined based on varying duration in literature. The primary objective was to determine the risk of poor outcomes in relation to bacteremia duration. METHODS: Multicenter, prospective, observational study of adult hospitalized patients with SAB. Medical records were reviewed for pertinent data. Patients were grouped by bacteremia duration: short (1-2 days), intermediate (3-6 days), and prolonged (≥7 days) and compared for risk factors and outcomes. RESULTS: Of 884 patients, 63% had short, 28% intermediate, and 9% prolonged bacteremia. Overall mean age was 57 years, and 70% were male. The prolonged group had the highest proportion of methicillin-resistant SAB (P < .0001). Choice of antibiotic therapy did not significantly affect bacteremia duration; however, time to source-control procedure was delayed in the prolonged and intermediate groups compared with the short group (3.5 vs 3 vs 1 day, P < .0001). Metastatic complications, length of stay, and 30-day mortality were progressively worse as bacteremia duration increased (P < .0001). Every continued day of bacteremia was associated with a relative risk of death of 1.16 (95% confidence interval, 1.10-1.22; P < .0001), with a significant increase in risk starting at 3 days as determined by receiver operating characteristic analysis. CONCLUSIONS: Optimal management of SAB should target bacterial clearance as soon as possible to minimize incremental risk of mortality with each day of positive blood culture. Delay in source control but not type of antistaphylococcal therapy was significantly associated with prolonged bacteremia and worse outcomes.

Surgical Method for Implantation of a Biosynthetic Retinal Pigment Epithelium Monolayer for Geographic Atrophy: Experience from a Phase 1/2a Study.

PURPOSE: To report the intraoperative methods and anatomic results for subretinal implantation of an investigational human embryonic stem cell-derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate (California Project to Cure Blindness Retinal Pigment Epithelium 1 [CPCB-RPE1]) in geographic atrophy (GA). DESIGN: Single-arm, open label, prospective, nonrandomized, Phase 1/2a study. PARTICIPANTS: Advanced non-neovascular age-related macular degeneration (NNAMD). METHODS: The worse-seeing eye (≤20/200) of each subject underwent subretinal implantation of a single 3.5×6.25 mm CPCB-RPE1 implant with a preplanned primary end point of safety and efficacy at 365 days. Commercially available 23-gauge vitrectomy equipment, custom surgical forceps, and operating microscope with or without intraoperative OCT (iOCT) were used. Exact Wilcoxon rank-sum tests and Spearman rank correlation coefficients were used to assess the association of the percentage of the GA area covered by the implant with patient and surgery characteristics. The partial Spearman correlation coefficient was calculated for the correlation between duration of surgery and baseline GA size after adjustment for surgeon experience. MAIN OUTCOME MEASURES: Intraoperative exploratory measures are reported, including area of GA covered by implant, subretinal position of implant, duration of surgery, and incidence of adverse events. Operative recordings and reports were used to determine exploratory outcome measures. RESULTS: Sixteen subjects were enrolled with a median age of 78 years (range, 69-85 years). Median duration of the surgery for all subjects was 160 minutes (range, 121-466 minutes). Intraoperative OCT was used to guide subretinal placement in 9 cases. Intraoperative OCT was potentially useful in identifying pathology not evident with standard intraoperative visualization. Median GA area at baseline was 13.8 mm2 (range, 6.0-46.4 mm2), and median GA area left uncovered by the implant was 1.7 mm2 (range, 0-20.4 mm2). On average, 86.9% of the baseline GA area was covered by the implant. In 5 subjects, >90% of the GA area was covered. Baseline GA size was inversely correlated with percentage of GA area covered by the implant (rs=-0.72; P = 0.002). No unanticipated serious adverse events related to the implant or surgery were reported. CONCLUSIONS: Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. Intraoperative OCT is not necessary but potentially useful in identifying subretinal pathology and confirming implant location.

Expanding Access to Home-Based Palliative Care: A Randomized Controlled Trial Protocol.

Introduction: Studies show that home-based palliative care (HBPC) improves participant outcomes and satisfaction with care while also decreasing hospitalizations and emergency department visits. U.S. health care payment reforms create financial opportunities to offer HBPC. Consequently, more HBPC programs are emerging, heightening the need to evaluate their effectiveness. Methods: This randomized, controlled trial is comparing the effectiveness of an evidence-based model of HBPC and enhanced usual primary care for participants who receive primary care from medical groups and clinics organized under an accountable care organization or Medicare Advantage plan. Palliative care services are reimbursed by our partnering health plan provider. The five-year trial will enroll 1155 seriously ill participants (and ∼884 of their caregivers) with heart failure, chronic obstructive pulmonary disease, or advanced cancer. We are collecting data via telephone surveys with participants at baseline and one and two months postenrollment and with caregivers at baseline, one and two months postenrollments, and following the death of a loved one. We are collecting participant-reported outcome measures of pain, symptoms, anxiety, depression, participant-provider communication, and hope. Caregiver outcome measures include caregiver burden, communication with providers, anxiety, and depression. Additional outcomes are participant survival time and participants' emergency department visits and hospitalizations. Study Implementation: Challenges and Contributions: Our research team has encountered several significant challenges in early study implementation. These include engaging primary care providers in the study and coordinating logistics with a health plan. Both challenges have contributed to a lag in participant enrollment. Despite these challenges, our study holds tremendous promise to accelerate adoption and spread of an evidence-based HBPC model across the country.

Interactive Education is Associated With Lower Incidence of Pedestrian-Related Injury in Children.

BACKGROUND: Pedestrian-related injuries are a significant contributor to preventable mortality and disability in children. We hypothesized that interactive pedestrian safety education is associated with increased knowledge, safe crosswalk behaviors, and lower incidence of pedestrian-related injuries in elementary school-aged children. METHODS: An interactive street-crossing simulation was implemented at target elementary schools in Los Angeles County beginning in 2009. Mixed-methods were used to evaluate the impact of this intervention. Multiple-choice examinations were used to test pedestrian safety knowledge, anonymous observations were used to assess street-crossing behaviors, and statewide traffic records were used to report pedestrian injuries in elementary school-aged (4-11 y) children in participating school districts. Pedestrian injury incidence was compared 1 y before and after the intervention, standardized to the incidence in the entire City of Los Angeles. RESULTS: A total of 1424 and 1522 children completed the pretest and post-test, respectively. Correct answers increased for nine of ten questions (all P < 0.01). Children more frequently looked both ways before crossing the street after the intervention (10% versus 41%, P < 0.001). There were 6 reported pedestrian-related injuries in intervention school districts in the year before the intervention and 2 injuries in the year after the intervention, resulting in a significantly lower injury incidence (standardized rate ratio 0.28; 95% CI, 0.11-0.73). CONCLUSION: Pedestrian safety education at Los Angeles elementary schools was associated with increased knowledge, safe street-crossing behavior, and lower incidence of pediatric pedestrian-related injury. Formal pedestrian safety education should be considered with injury prevention efforts in similar urban communities.

Identification of Developmental Delay in Infants Using Wearable Sensors: Full-Day Leg Movement Statistical Feature Analysis.

This paper examines how features extracted from full-day data recorded by wearable sensors are able to differentiate between infants with typical development and those with or at risk for developmental delays. Wearable sensors were used to collect full-day (8-13 h) leg movement data from infants with typical development ([Formula: see text]) and infants at risk for developmental delay ([Formula: see text]). At 24 months, at-risk infants were assessed as having good ([Formula: see text]) or poor ([Formula: see text]) developmental outcomes. With this limited size dataset, our statistical analysis indicated that accelerometer features collected earlier in infancy differentiated between at-risk infants with poor and good outcomes at 24 months, as well as infants with typical development. This paper also tested how these features performed on a subset of the data for which the infant movement was known, i.e., 5-min intervals more representative of clinical observations. Our results on this limited dataset indicated that features for full-day data showed more group differences than similar features for the 5-min intervals, supporting the usefulness of full-day movement monitoring.