Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116).

PURPOSE: To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS: Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS: Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION: BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial.

Importance: Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective: To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants: A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions: Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures: Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results: A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance: The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial Registration: ClinicalTrials.gov Identifier: NCT02589938.

Incidence, Predictors, and Impact of Hospital Readmission After Revascularization for Left Main Coronary Disease.

BACKGROUND: The frequency of and relationship between hospital readmissions and outcomes after revascularization for left main coronary artery disease (LMCAD) are unknown. OBJECTIVES: The purpose of this study was to study the incidence, predictors, and clinical impact of readmissions following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for LMCAD. METHODS: In the EXCEL (XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, 1,905 patients with LMCAD were randomized to PCI vs CABG. The cumulative incidence of readmissions was analyzed with multivariable Anderson-Gill and joint frailty models to account for recurrent events and the competing risk of death. The impact of readmission on subsequent mortality within 5-year follow-up was determined in a time-adjusted Cox proportional hazards model. RESULTS: Within 5 years, 1,868 readmissions occurred in 851 of 1,882 (45.2%) hospital survivors (2.2 ± 1.9 per patient with readmission[s], range 1-16), approximately one-half for cardiovascular causes and one-half for noncardiovascular causes (927 [49.6%] and 941 [50.4%], respectively). One or more readmissions occurred in 463 of 942 (48.6%) PCI patients vs 388 of 940 (41.8%) CABG patients (P = 0.003). After multivariable adjustment, PCI remained an independent predictor of readmission (adjusted HR: 1.22; 95% CI: 1.10-1.35; P < 0.0001), along with female sex, comorbidities, and the extent of CAD. Readmission was independently associated with subsequent all-cause death, with interaction testing indicating a higher risk after PCI than CABG (adjusted HR: 5.72; 95% CI: 3.42-9.55 vs adjusted HR: 2.72; 95% CI: 1.64-4.88, respectively; Pint = 0.03). CONCLUSIONS: In the EXCEL trial, readmissions during 5-year follow-up after revascularization for LMCAD were common and more frequent after PCI than CABG. Readmissions were associated with an increased risk of all-cause death, more so after PCI than with CABG.

Rural EMS STEMI Patients - Why the Delay to PCI?

BACKGROUND: The objective of this study is to identify patient and EMS agency factors associated with timely reperfusion of patients with ST-elevation myocardial infarction (STEMI). METHODS: We conducted a cohort study of adult patients (≥18 years old) with STEMI activations from 2016 to 2020. Data was obtained from a regional STEMI registry, which included eight rural county EMS agencies and three North Carolina percutaneous coronary intervention (PCI) centers. On each patient, prehospital and in-hospital time intervals were abstracted. The primary outcome was the ability to achieve the 90-minute EMS FMC to PCI time goal (yes vs. no). We used generalized estimating equations accounting for within-agency clustering to evaluate the association between patient and agency factors and meeting first medical contact (FMC) to PCI time goal while accounting for clustering within the agency. RESULTS: Among 365 rural STEMI patients 30.1% were female (110/365) with a mean age of 62.5 ± 12.7 years. PCI was performed within the time goal in 60.5% (221/365) of encounters. The FMC to PCI time goal was met in 45.5% (50/110) of women vs 69.8% (178/255) of men (p < 0.001). The median PCI center activation time was 12 min (IQR 7-19) in the group that received PCI within the time goal compared to 21 min (IQR 10-37) in the cohort that did not. After adjusting for loaded mileage and other clinical variables (e.g., pulse rate, hypertension etc.), the male sex was associated with an improved chance of meeting the goal of FMC to PCI (aOR: 2.94; 95% CI 2.11-4.10) compared to the female sex. CONCLUSION: Nearly 40% of rural STEMI patients transported by EMS failed to receive FMC to PCI within 90 min. Women were less likely than men to receive reperfusion within the time goal, which represents an important health care disparity.

Effects of mycobacterium cell wall fraction on embryo development following in vitro embryo production and pregnancy rates following embryo transfer in virgin dairy heifers.

An experiment was conducted to determine whether administration of mycobacterium cell wall fraction (MCWF; Amplimune, NovaVive) could enhance embryo developmental competence following in vitro embryo production (IVP) and pregnancy establishment after embryo transfer (ET). Nulliparous, Holstein heifers (n = 40; age 8-15 months) were submitted to two rounds of ovum pick-up (OPU) and IVP in a crossover design. Thirty-six h after follicle wave synchronization, treatments (saline or MCWF, 5 mL, im) were administered in conjunction with a single dose of follicle stimulating hormone (175 IU) and OPU was performed 48-52 h later. Recovered cumulus-oocyte complexes were used for IVP to assess embryo development. For ET, nulliparous, Holstein heifers (n = 225; age 12-18 months) were used as recipients. At 12-24 h after detection of spontaneous estrus, recipients were randomly treated with either saline or MCWF (5 mL, im). The effect of MCWF on pregnancy per ET (P/ET) was assessed in a 2 × 2 factorial design with recipients treated with or without MCWF receiving a fresh IVP embryo from a donor treated with or without MCWF at day 7 or 8 after detected estrus. Blood samples were collected from a subset of donors (n = 8) and recipients (n = 26 to 33 per treatment) prior to treatment and at 6 and 24 h post-treatment to determine serum concentration of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and interferon-γ. Blood samples were also collected from a group of recipients (n = 31 to 39 per treatment) to assess serum concentration of progesterone at days 4, 7, and 16 post-treatment. Pregnancy status was determined at days 40 and 100 of gestation. Donor treatment with MCWF tended (P < 0.07) to increase the proportion of oocytes that developed into transferable embryos, but there was no effect of MCWF on other parameters of embryo development. The P/ET at days 40 and 100 of gestation and pregnancy loss were not affected by donor treatment or recipient treatment with MCWF and there was no interaction. Serum concentration of proinflammatory cytokines among donors and recipients and serum concentration of progesterone among recipients were not increased by treatment with MCWF. Results of the present study indicate that treatment of donors with MCWF has minimal impact on subsequent embryo development following IVP. Moreover, regardless of whether donors or recipients were treated with MCWF, there was no effect on P/ET following transfer of IVP embryos.

Percutaneous ventricular assist device for higher-risk percutaneous coronary intervention in surgically ineligible patients: Indications and outcomes from the OPTIMUM study.

BACKGROUND: Indications and outcomes for percutaneous ventricular assist device (pVAD) use in surgically ineligible patients undergoing percutaneous coronary intervention (PCI) remain poorly characterized. AIMS: We sought to describe the use and timing of pVAD and outcome in surgically ineligible patients. METHODS: Among 726 patients enrolled in the prospective OPTIMUM study, clinical and health status outcomes were assessed in patients who underwent pVAD-assisted PCI and those without pVAD. RESULTS: Compared with patients not receiving pVAD (N = 579), those treated with pVAD (N = 142) more likely had heart failure, lower left ventricular ejection fraction (30.7 ± 13.6 vs. 45.9 ± 15.5, p < 0.01), and higher STS 30-day predicted mortality (4.2 [2.1-8.0] vs. 3.3 [1.7-6.6], p = 0.01) and SYNTAX scores (36.1 ± 12.2, vs. 31.5 ± 12.1, p < 0.01). While the pVAD group had higher in-hospital (5.6% vs. 2.2%, p = 0.046), 30-day (9.0% vs. 4.0%, p = 0.01) and 6-month (20.4% vs. 11.7%, p < 0.01) mortality compared to patients without pVAD, this difference appeared to be largely driven by significantly higher mortality among the 20 (14%) patients with unplanned pVAD use (30% in-hospital mortality with unplanned PVAD vs. 1.6% with planned, p < 0.01; 30-day mortality, 38.1% vs. 4.5%, p < 0.01). The degree of 6-month health status improvement among survivors was similar between groups. CONCLUSION: Surgically ineligible patients with pVAD-assisted PCI had more complex baseline characteristics compared with those without pVAD. Higher mortality in the pVAD group appeared to be driven by very poor outcomes by patients with unplanned, rescue pVAD.

Increasing the prepartum dose of rumen-protected choline: Effects of maternal choline supplementation on growth, feed efficiency, and metabolism in Holstein and Holstein × Angus calves.

Feeding pregnant cows rumen-protected choline (RPC) may have the potential to affect the growth and health of offspring, but little is known about the optimal dose, or the potential mechanisms of action. The objectives of this experiment were to 1) determine if increasing RPC supplementation during late gestation in multiparous Holstein cows would improve calf growth and 2) determine if maternal choline supplementation alters global DNA methylation patterns. Pregnant multiparous Holstein cows (n = 116) were randomly assigned to diets targeting 0g choline ion (0.0 ± 0.000 choline ion, %DM, control; CTL), 15g of choline ion (recommended dose; RD) from an established RPC product (0.10 ± 0.004 choline ion, %DM, RPC1RD; ReaShure, Balchem Corp.; positive control), or 15g (0.09 ± 0.004 choline ion, %DM, RPC2RD) or 22g (0.13 ± 0.005 choline ion, %DM, high dose; RPC2HD) of choline ion from a concentrated RPC prototype (RPC2; Balchem Corp.). Treatments were mixed into a total mixed ration and cows had ad libitum access via a roughage intake control system (Hokofarm Group, Marknesse, Netherlands). All female Holstein (n = 49) and Holstein × Angus calves (male, n = 18; female, n = 30) were enrolled and fed colostrum from a cow within the same treatment. Holstein calves and Holstein × Angus calves were fed an accelerated and traditional milk replacer program, respectively, and offered ad libitum access to calf starter. Jugular vein blood samples were collected, and body weight was measured at 7, 14, 28, 42, and 56 d of age. Categorical treatment and continuous effects of actual prepartum maternal choline ion intake were analyzed using mixed effect models. An interaction of treatment with sex, nested within breed, resulted in any choline treatment increasing the proportion of methylated whole blood DNA in male, but not female calves. Although 37% of Holstein calves across all treatments experienced abomasal bloat, no evidence for differences in health measurements (signs of respiratory disease and fecal consistency) were observed across treatments. During the first 2 wk of life in Holstein calves, RPC2HD tended to increase average daily gain (ADG) and feed efficiency (FE) compared with CTL and increasing maternal choline ion intake linearly increased ADG and FE. Maternal choline supplementation increased plasma glucose compared with CTL, while increasing serum insulin-like growth factor-1 and decreasing serum lipopolysaccharide binding protein at 7 d of age in Holstein calves. In Holstein × Angus calves, the effect of treatment on ADG tended to interact with sex: in males, RPC2HD increased ADG after 2 wk of life compared with CTL, without evidence of a treatment effect in female calves. Increasing maternal choline ion intake linearly increased ADG after 2 wk of age in male Holstein × Angus calves, while quadratically increasing FE in both sexes. Altered global DNA methylation patterns in male Holstein × Angus calves, and changes in blood metabolites in Holstein calves, provide 2 potential mechanisms for observed improvements in calf growth. Continuous treatment models demonstrated that the effects of maternal choline supplementation are sensitive to the amount of maternal choline ion intake, with greater benefit to calves observed at higher maternal intakes.

Increasing the prepartum dose of rumen-protected choline: Effects on milk production and metabolism in high-producing Holstein dairy cows.

Peripartum rumen-protected choline (RPC) supplementation is beneficial for cow health and production, yet the optimal dose is unknown. In vivo and in vitro supplementation of choline modulates hepatic lipid, glucose, and methyl donor metabolism. The objective of this experiment was to determine the effects of increasing the dose of prepartum RPC supplementation on milk production and blood biomarkers. Pregnant multiparous Holstein cows (n = 116) were randomly assigned to one of 4 prepartum choline treatments that were fed from -21 d relative to calving (DRTC) until calving. From calving until +21 DRTC, cows were fed diets targeting 0 g/d choline ion (control, CTL) or the recommended dose (15 g/d choline ion; RD) of the same RPC product that they were fed prepartum. The resulting treatments targeted: (1) 0 g/d pre- and postpartum [0.0 ± 0.000 choline ion, percent of dry matter (%DM); CTL]; (2) 15 g/d pre- and postpartum of choline ion from an established product (prepartum: 0.10 ± 0.004 choline ion, %DM; postpartum: 0.05 ± 0.004 choline ion, %DM; ReaShure, Balchem Corp.; RPC1RD▸RD); (3) 15 g/d pre- and postpartum of choline ion from a concentrated RPC prototype (prepartum: 0.09 ± 0.004 choline ion, %DM; postpartum: 0.05 ± 0.003 choline ion, %DM; RPC2, Balchem Corp.; RPC2RD▸RD); or (4) 22 g/d prepartum and 15 g/d postpartum from RPC2 [prepartum: 0.13 ± 0.005 choline ion, %DM; postpartum: 0.05 ± 0.003 choline ion, %DM; high prepartum dose (HD), RPC2HD▸RD]. Treatments were mixed into a total mixed ration, and cows had ad libitum access via a roughage intake control system (Hokofarm Group). From calving to +21 DRTC, all cows were fed a common base diet and treatments were mixed into the total mixed ration (supplementation period, SP). Thereafter, all cows were fed a common diet (0 g/d choline ion) until +100 DRTC (postsupplementation period, postSP). Milk yield was recorded daily and composition analyzed weekly. Blood samples were obtained via tail vessel upon enrollment, approximately every other day from -7 to +21 DRTC, and at +56 and +100 DRTC. Feeding any RPC treatment reduced prepartum dry matter intake compared with CTL. During the SP, no evidence for a treatment effect on energy-corrected milk (ECM) yield was found, but during the postSP, RPC1RD▸RD and RPC2RD▸RD treatments tended to increase ECM, protein, and fat yields. During the postSP, the RPC1RD▸RD and RPC2RD▸RD treatments tended to increase, and RPC2HD▸RD increased, the de novo proportion of total milk fatty acids. During the early lactation SP, RPC2HD▸RD tended to increase plasma fatty acids and ß-hydroxybutyrate concentrations, and RPC1RD▸RD and RPC2RD▸RD reduced blood urea nitrogen concentrations compared with CTL. The RPC2HD▸RD treatment reduced early lactation serum lipopolysaccharide binding protein compared with CTL. Overall, peripartum RPC supplementation at the recommended dose tended to increase ECM yield postSP, but no evidence was seen of an additional benefit on milk production with an increased prepartum dose of choline ion. The effects of RPC on metabolic and inflammatory biomarkers support the potential for RPC supplementation to affect transition cow metabolism and health and may support the production gains observed.

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Reducing Anxiety and Dyspnea via Device-Guided Breathing (RELAX): A Multi-Site Feasibility Study in Post-Treatment Lung Cancer Survivors at Community Cancer Clinics (WF-01213).

INTRODUCTION: Anxiety and dyspnea are 2 common symptoms for lung cancer survivors. Although research suggests decreasing respiration rate can reduce anxiety in several populations, potential benefits of device-guided breathing have not been studied in lung cancer survivors. This feasibility study (WF-01213) provides estimates of accrual, adherence, retention, and preliminary efficacy of 2 doses of a device-guided breathing intervention versus a usual breathing control group for improving self-reported anxiety and dyspnea in post-treatment lung cancer survivors. METHODS: Stage I-IV lung cancer survivors were recruited through the NCI Community Oncology Research Program (NCORP) and randomized to 12 weeks of a device-guided breathing intervention (high dose vs. low dose) or control device. Self-reported outcomes (anxiety, depression, dyspnea, cancer-related worry, fatigue) were assessed at baseline, mid-intervention (Week-6), and post-intervention (Week-12). RESULTS: Forty-six participants (ages 41-77, median = 65; 78% White) were randomized to the high-dose intervention (n = 14), low-dose intervention (n = 14), or control (n = 18) groups between July 2015 and September 2019. Study accrual rate was 0.92 per month for 50 months (projected accrual was 6.3/month). Fourteen participants (30%) withdrew early from the study, with almost half of those discontinuing at or immediately following baseline assessment. No participants were adherent with the intervention per protocol specifications. The proportion minimally adherent (using device at least 1x/week) was 43% (6/14), 64% (9/14), and 61% (11/18) for high-dose, low-dose, and control groups, respectively. Anxiety significantly decreased from baseline for all groups at Week 12. Adherence to the intervention was low across all treatment groups. CONCLUSIONS: This study did not establish feasibility of a community-based randomized trial of 2 doses of device-guided breathing and a control group using an identical-looking device for lung cancer survivors. In both the high-dose and control groups, there were significant improvements from baseline for anxiety and dyspnea. In the low-dose group, there were significant improvements from baseline for anxiety and depression. Ratings and feedback on the intervention were mixed (although leaned in a positive direction). Participants reported liking the feeling of relaxation/calm, helping others, breathing awareness, and music. Participants reporting liking least finding/making time to use the device, frustration with the device, and completing study forms. TRIAL REGISTRATION: CLINICAL TRIALS ID: NCT02063828, clinicaltrials.gov.

Outcomes of Medical Therapy Plus PCI for Multivessel or Left Main CAD Ineligible for Surgery.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly used to revascularize patients ineligible for CABG, but few studies describe these patients and their outcomes. OBJECTIVES: This study sought to describe characteristics, utility of risk prediction, and outcomes of patients with left main or multivessel coronary artery disease ineligible for coronary bypass grafting (CABG). METHODS: Patients with complex coronary artery disease ineligible for CABG were enrolled in a prospective registry of medical therapy + PCI. Angiograms were evaluated by an independent core laboratory. Observed-to-expected 30-day mortality ratios were calculated using The Society for Thoracic Surgeons (STS) and EuroSCORE (European System for Cardiac Operative Risk Evaluation) II scores, surgeon-estimated 30-day mortality, and the National Cardiovascular Data Registry (NCDR) CathPCI model. Health status was assessed at baseline, 1 month, and 6 months. RESULTS: A total of 726 patients were enrolled from 22 programs. The mean SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score was 32.4 ± 12.2 before and 15.0 ± 11.7 after PCI. All-cause mortality was 5.6% at 30 days and 12.3% at 6 months. Observed-to-expected mortality ratios were 1.06 (95% CI: 0.71-1.36) with The Society for Thoracic Surgeons score, 0.99 (95% CI: 0.71-1.27) with the EuroSCORE II, 0.59 (95% CI: 0.42-0.77) using cardiac surgeons' estimates, and 4.46 (95% CI: 2.35-7.99) using the NCDR CathPCI score. Health status improved significantly from baseline to 6 months: SAQ summary score (65.9 ± 22.5 vs 86.5 ± 15.1; P < 0.0001), Kansas City Cardiomyopathy Questionnaire summary score (54.1 ± 27.2 vs 82.6 ± 19.7; P < 0.0001). CONCLUSIONS: Patients ineligible for CABG who undergo PCI have complex clinical profiles and high disease burden. Following PCI, short-term mortality is considerably lower than surgeons' estimates, similar to surgical risk model predictions but is over 4-fold higher than estimated by the NCDR CathPCI model. Patients' health status improved significantly through 6 months.

Impact of Periprocedural Adverse Events After PCI and CABG on 5-Year Mortality: The EXCEL Trial.

BACKGROUND: The relative risks for different periprocedural major adverse events (MAE) after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on subsequent mortality have not been described. OBJECTIVES: The aim of this study was to assess the association between periprocedural MAE occurring within 30 days postprocedure and early and late mortality after left main coronary artery revascularization by PCI and CABG. METHODS: In the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, patients with left main disease were randomized to PCI vs CABG. The associations between 12 prespecified nonfatal MAE and subsequent 5-year all-cause and cardiovascular death in 1,858 patients were examined using logistic regression. RESULTS: One or more nonfatal MAE occurred in 111 of 935 patients (11.9%) after PCI and 419 of 923 patients (45.4%) after CABG (P < 0.0001). Patients with MAE were older and had more baseline comorbidities. Within 5 years, all-cause death occurred in 117 and 87 patients after PCI and CABG, respectively. Experiencing an MAE was a strong independent predictor of 5-year mortality after both PCI (adjusted OR: 4.61; 95% CI: 2.71-7.82) and CABG (adjusted OR: 3.25; 95% CI: 1.95-5.41). These associations were present within the first 30 days and between 30 days and 5 years postprocedure. Major or minor bleeding with blood transfusion ≥2 U was an independent predictor of 5-year mortality after both procedures. Stroke, unplanned revascularization for ischemia, and renal failure were significantly associated with mortality only after CABG. CONCLUSIONS: In the EXCEL trial, nonfatal periprocedural MAE were strongly associated with early and late mortality after both PCI and CABG for left main disease.

Modeling community COVID-19 transmission risk associated with U.S. universities.

The ongoing COVID-19 pandemic is among the worst in recent history, resulting in excess of 520,000,000 cases and 6,200,000 deaths worldwide. The United States (U.S.) has recently surpassed 1,000,000 deaths. Individuals who are elderly and/or immunocompromised are the most susceptible to serious sequelae. Rising sentiment often implicates younger, less-vulnerable populations as primary introducers of COVID-19 to communities, particularly around colleges and universities. Adjusting for more than 32 key socio-demographic, economic, and epidemiologic variables, we (1) implemented regressions to determine the overall community-level, age-adjusted COVID-19 case and mortality rate within each American county, and (2) performed a subgroup analysis among a sample of U.S. colleges and universities to identify any significant preliminary mitigation measures implemented during the fall 2020 semester. From January 1, 2020 through March 31, 2021, a total of 22,385,335 cases and 374,130 deaths were reported to the CDC. Overall, counties with increasing numbers of university enrollment showed significantly lower case rates and marginal decreases in mortality rates. County-level population demographics, and not university level mitigation measures, were the most significant predictor of adjusted COVID-19 case rates. Contrary to common sentiment, our findings demonstrate that counties with high university enrollments may be more adherent to public safety measures and vaccinations, likely contributing to safer communities.

Chronic Invasive Fungal Sinusitis With Negative Histopathology: A Diagnostic Challenge.

Although the diagnosis of chronic invasive fungal sinusitis relies chiefly on identification of invasive fungi on histology, the insidious nature of the disease can preclude detection of fungal organisms. Here, we present a case of chronic invasive fungal sinusitis with negative histopathologic findings and a definitive diagnosis made through fungal DNA detection. Clinicians should consider polymerase chain reaction an important complement to histology and culture in the diagnosis of chronic invasive fungal sinusitis.

Levels of physical activity and sitting time in women with infants, toddlers and preschoolers: a population-based cross-sectional study.

OBJECTIVES: Insufficient physical activity (PA) and prolonged sitting time (ST) increase the risk of chronic disease and mortality. Caring for young children can potentially impact maternal PA and sedentary behaviours. The aims of this study were to explore the levels of PA and ST in women with young children (infants, toddlers and preschoolers) and sociodemographic and behavioural factors associated with these. STUDY DESIGN: This was a population-based cross-sectional study. METHODS: Survey 5 data collected in 2009 (n = 4290) of the 1973-1978 birth cohort of the Australian Longitudinal Study on Women's Health were used. Multiple linear and logistic regression models were used to examine associations. RESULTS: In adjusted models, compared with women with preschoolers, women whose youngest child was an infant aged 0-6 months, aged >6-12 months or toddler had lower PA (-321.3 MET.min/week [95% confidence interval (CI) -416.2, -226.4], -147.9 MET.min/week [95% CI -237.6, -58.1] and -106.4 MET.min/week [95% CI -172.3, -40.5]). ST was higher in women whose youngest child was an infant aged 0-6 months (0.48 h/day; 95% CI 0.19, 0.77) but lower with infants aged >6-12 months (-0.33 h/day; 95% CI -0.60, -0.05) and toddlers (-0.40 h/day; 95% CI -0.60, -0.20) than in those with preschoolers. The findings were similar in the logistic model. Sociodemographic and behavioural factors such as occupation and marital status also influenced PA and ST. CONCLUSIONS: Women with infants and toddlers have lower PA than women with preschoolers. Women are more likely to sit more in the first 6 months after childbirth. These findings can inform resources and intervention development to improve activity levels in women with young children through consideration of the age of the youngest child, sociodemographic and behavioural factors.

Predicting dry matter intake in mid-lactation Holstein cows using point-in-time data streams available on dairy farms.

Quantifying dry matter intake (DMI) in lactating dairy cows is important for determining feed efficiency; however, there are no methods for economically quantifying individual cow DMI on dairy farms where cows are group-fed. Attempts have been made to model DMI using cow factors, milk production, milk infrared spectra, and behavioral sensors with reasonable success. Other data streams are available on the farm that may contribute to DMI predictions. In this study, our objective was to model DMI with multiple linear regression using data from a single point-in-time that can easily be accessed on-farm. Candidate predictor variables included cow descriptors, milk yield and composition, milk fatty acid profile, and production and efficiency predicting transmitting abilities (PTA). Observations of DMI were obtained from 350 cows across 6 cohorts using individual feed bunks. The cow to bunk ratio was 2:1, with an overall bunk occupation rate of 32% throughout the day. The following models were developed sequentially with milk data obtained from a single morning milking and other data from the same day: model B (production, metabolic body weight, body condition score, lactation category, and week of lactation), model BC [model B + fatty acid (FA) content], model BY (model B + FA yield), model BPE (model B + production and efficiency PTA), model BYP (model BY + production PTA), model BYE (model BY + efficiency PTA), and model BYPE (model BY + production and efficiency PTA). Outcome variables predicted in these models were the DMI on the previous day or current day relative to the morning milk sample. The predictions for DMI on the previous day outperformed current day DMI in every model for which they were both determined. Addition of milk FA and PTA as candidate predictor variable types to the models resulted in enhanced predictive ability, with incremental enhancements when combined. The most robust model (BYPE) included cow descriptors, protein and FA yields, and PTA for milk and residual feed intake. Model BYPE described 21 to 32% more of the variation in DMI (based on concordance correlation coefficient) than when other common DMI models were applied to the same data set. Overall, reasonable performance of models including single point-in-time cow descriptors, milk and FA production, and production and efficiency PTA commonly available to dairy farmers through dairy herd improvement programs offer an opportunity for on-farm prediction of DMI, yet further improvement may be possible.

Feeding behavior parameters and temporal patterns in mid-lactation Holstein cows across a range of residual feed intake values.

Residual feed intake (RFI) is a measurement of the difference between actual and predicted feed intake when adjusted for energy sinks; more efficient cows eat less than predicted (low RFI) and inefficient cows eat more than predicted (high RFI). Data evaluating the relationship between RFI and feeding behaviors (FB) are limited in dairy cattle; therefore, the objective of this study was to determine daily and temporal FB in mid-lactation Holstein cows across a range of RFI values. Mid-lactation Holstein cows (n = 592 multiparous; 304 primiparous) were enrolled in 17 cohorts at 97 ± 26 d in milk (± standard deviation), and all cows within a cohort were fed a common diet using automated feeding bins. Cow RFI was calculated as the difference between predicted and observed dry matter intake (DMI) after accounting for parity, days in milk, milk energy, metabolic body weight and change, and experiment. The associations between RFI and FB at the level of meals and daily totals were evaluated using mixed models with the fixed effect of RFI and the random effects of cow and cohort. Daily temporal FB analyses were conducted using 2-h blocks and analyzed using mixed models with the fixed effects of RFI, time, RFI × time, and cohort, and the random effect of cow (cohort). There was a positive linear association between RFI and DMI in multiparous cows and a positive quadratic relationship in primiparous cows, where the rate of increase in DMI was less at higher RFI. Eating rate, DMI per meal, and size of the largest daily meal were positively associated with RFI. Daily temporal analysis of FB revealed an interaction between RFI and time for eating rate in multiparous and primiparous cows. The eating rate increased with greater RFI at 11 of 12 time points throughout the day, and eating rate differed across RFI between multiple time points. There tended to be an interaction between RFI and time for eating time and bin visits in multiparous cows but not primiparous cows. Overall, there was a time effect for all FB variables, where DMI, eating time and rate, and bin visits were greatest after the initial daily feeding at 1200 h, increased slightly after each milking, and reached a nadir at 0600 h (6 h before feeding). Considering the relationship between RFI and eating rate, additional efforts to determine cost-effective methods of quantifying eating rate in group-housed dairy cows is warranted. Further investigation is also warranted to determine if management strategies to alter FB, especially eating rate, can be effective in increasing feed efficiency in lactating dairy cattle.

Prediction of nitrogen excretion from data on dairy cows fed a wide range of diets compiled in an intercontinental database: A meta-analysis.

Manure nitrogen (N) from cattle contributes to nitrous oxide and ammonia emissions and nitrate leaching. Measurement of manure N outputs on dairy farms is laborious, expensive, and impractical at large scales; therefore, models are needed to predict N excreted in urine and feces. Building robust prediction models requires extensive data from animals under different management systems worldwide. Thus, the study objectives were (1) to collate an international database of N excretion in feces and urine based on individual lactating dairy cow data from different continents; (2) to determine the suitability of key variables for predicting fecal, urinary, and total manure N excretion; and (3) to develop robust and reliable N excretion prediction models based on individual data from lactating dairy cows consuming various diets. A raw data set was created based on 5,483 individual cow observations, with 5,420 fecal N excretion and 3,621 urine N excretion measurements collected from 162 in vivo experiments conducted by 22 research institutes mostly located in Europe (n = 14) and North America (n = 5). A sequential approach was taken in developing models with increasing complexity by incrementally adding variables that had a significant individual effect on fecal, urinary, or total manure N excretion. Nitrogen excretion was predicted by fitting linear mixed models including experiment as a random effect. Simple models requiring dry matter intake (DMI) or N intake performed better for predicting fecal N excretion than simple models using diet nutrient composition or milk performance parameters. Simple models based on N intake performed better for urinary and total manure N excretion than those based on DMI, but simple models using milk urea N (MUN) and N intake performed even better for urinary N excretion. The full model predicting fecal N excretion had similar performance to simple models based on DMI but included several independent variables (DMI, diet crude protein content, diet neutral detergent fiber content, milk protein), depending on the location, and had root mean square prediction errors as a fraction of the observed mean values of 19.1% for intercontinental, 19.8% for European, and 17.7% for North American data sets. Complex total manure N excretion models based on N intake and MUN led to prediction errors of about 13.0% to 14.0%, which were comparable to models based on N intake alone. Intercepts and slopes of variables in optimal prediction equations developed on intercontinental, European, and North American bases differed from each other, and therefore region-specific models are preferred to predict N excretion. In conclusion, region-specific models that include information on DMI or N intake and MUN are required for good prediction of fecal, urinary, and total manure N excretion. In absence of intake data, region-specific complex equations using easily and routinely measured variables to predict fecal, urinary, or total manure N excretion may be used, but these equations have lower performance than equations based on intake.

Design and testing of the safety of the SARUS-CPR hood for novice resuscitators.

BACKGROUND AND AIMS: Bystanders should be protected against aerosols, droplets, saliva, blood and vomitus during resuscitation after cardiac arrest The SARUS (safer - airway - resuscitation) CPR airway hood™ is a clear plastic cover and integrated mask that envelopes the head and torso. Our objectives were to test leakage using saline aerosol generation tests, then assess the performance of the hood during mock cardio-pulmonary resuscitation on a manikin. METHODS: A checklist was validated by comparing the performance of 10 novices against 10 experts during mock resuscitation. Thereafter, 15 novices were tested with and without the hood, in a randomised cross-over study, one week apart. RESULTS: Laboratory analysis showed a > 99% reduction of saline particles detected 5 cm, 75 cm and 165 cm above volunteers wearing the hood. On manikins, experts scored better compared to novices, 8.5 (0.7) vs 7.6 (1.2), difference (95%CI) 0.9 (0.4-1.3), P = 0.0004. Novice performance was equivalent using the hood and standard equipment, 7.3 (1.4) vs 7.3 (1.1) respectively, difference (90%CI) 0.0 (-0.3 - 0.3), P = 0.90. CONCLUSION: Aerosol transmission reduced in the breathing zone. Simulated resuscitation by novices was equivalent with and without the hood.

3-Hydroxyacyl-CoA and Alcohol Dehydrogenase Activities of Mitochondrial Type 10 17ß-Hydroxysteroid Dehydrogenase in Neurodegeneration Study.

BACKGROUND: Mitochondrial 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aß-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aß-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17ß-HSD10. OBJECTIVE: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals. METHODS: 6xHis-tagged 17ß-HSD10 was prepared and characterized by well-established experimental procedures. RESULTS: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17ß-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports. CONCLUSION: Brain 17ß-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.