Flexible multifunctional titania nanotube array platform for biological interfacing.

Abstract: The current work presents a novel flexible multifunctional platform for biological interface applications. The use of titania nanotube arrays (TNAs) as a multifunctional material is explored for soft-tissue interface applications. In vitro biocompatibility of TNAs to brain-derived cells was first examined by culturing microglia cells-the resident immune cells of the central nervous system on the surface of TNAs. The release profile of an anti-inflammatory drug, dexamethasone from TNAs-on-polyimide substrates, was then evaluated under different bending modes. Flexible TNAs-on-polyimide sustained a linear release of anti-inflammatory dexamethasone up to ~11 days under different bending conditions. Finally, microfabrication processes for patterning and transferring TNA microsegments were developed to facilitate structural stability during device flexing and to expand the set of compatible polymer substrates. The techniques developed in this study can be applied to integrate TNAs or other similar nanoporous inorganic films onto various polymer substrates. Impact statement: Titania nanotube arrays (TNAs) are highly tunable and biocompatible structures that lend themselves to multifunctional implementation in implanted devices. A particularly important aspect of titania nanotubes is their ability to serve as nano-reservoirs for drugs or other therapeutic agents that slowly release after implantation. To date, TNAs have been used to promote integration with rigid, dense tissues for dental and orthopedic applications. This work aims to expand the implant applications that can benefit from TNAs by integrating them onto soft polymer substrates, thereby promoting compatibility with soft tissues. The successful direct growth and integration of TNAs on polymer substrates mark a critical step toward developing mechanically compliant implantable systems with drug delivery from nanostructured inorganic functional materials. Diffusion-driven release kinetics and the high drug-loading efficiency of TNAs offer tremendous potential for sustained drug delivery for scientific investigations, to treat injury and disease, and to promote device integration with biological tissues. This work opens new opportunities for developing novel and more effective implanted devices that can significantly improve patient outcomes and quality of life. Supplementary information: The online version contains supplementary material available at 10.1557/s43577-023-00628-y.

Effects of Micromachining on Anti-oxidant Elution from a Mechanically-Adaptive Polymer.

Intracortical microelectrodes (IMEs) can be used to restore motor and sensory function as a part of brain-computer interfaces in individuals with neuromusculoskeletal disorders. However, the neuroinflammatory response to IMEs can result in their premature failure, leading to reduced therapeutic efficacy. Mechanically-adaptive, resveratrol-eluting (MARE) neural probes target two mechanisms believed to contribute to the neuroinflammatory response by reducing the mechanical mismatch between the brain tissue and device, as well as locally delivering an antioxidant therapeutic. To create the mechanically-adaptive substrate, a dispersion, casting, and evaporation method is used, followed by a microfabrication process to integrate functional recording electrodes on the material. Resveratrol release experiments were completed to generate a resveratrol release profile and demonstrated that the MARE probes are capable of long-term controlled release. Additionally, our results showed that resveratrol can be degraded by laser-micromachining, an important consideration for future device fabrication. Finally, the electrodes were shown to have a suitable impedance for single-unit neural recording and could record single units in vivo.

Progression of cardiac structure and function in people with human immunodeficiency virus.

OBJECTIVE: People living with HIV (PLWH) are at increased risk for cardiac dysfunction. It is unknown how their global longitudinal cardiac function, cardiac structure, and other indices of function progress over time. We aimed to characterize the longitudinal trend in cardiac structure and function in PLWH. DESIGN: Retrospective study of PLWH with clinically obtained echocardiograms at an academic medical center. METHODS: We reviewed archived transthoracic echocardiograms (TTEs) performed between 2001 and 2012 on PLWH. The primary outcome measures were progression of global longitudinal strain (GLS, left and right ventricles), LV mass, E/e' ratio, LV end-systolic, and -diastolic volumes using hierarchical mixed model analysis as a function of CD4+ T cell count and HIV RNA suppression. Models were adjusted for clinical and demographic characteristics. RESULTS: We analyzed 469 TTEs from 150 individuals (median age 46 years, 58% male). Median CD4+ T cell counts at nadir and proximal to first echocardiogram were 85 and 222 cells/mm3 , respectively. Over a median of 5 years, LV mass index increased regardless of nadir or proximal CD4+ T cell count or viral suppression status. PLWH with viral suppression at baseline had more normal GLS throughout the follow-up period. There were no significant trends in LV end-systolic volume index or E/e'. CONCLUSIONS: In PLWH, HIV viral suppression is associated with early gains in echocardiographic indices of cardiac function that persist for up to >5 years. HIV disease control impacts routine echocardiographic measures with known impacts on long-term prognosis.

Irreversible, Self-Aligned Microfluidic Packaging for Chronic Implant Applications.

Packaging is an often overlooked component in microfluidic devices for biomedical implant applications. Robust and reliable connectors to interface microscale and macroscale features are especially critical for chronic implant applications. Existing microfluidic packaging methods are incompatible with emerging polymeric materials designed to enhance device integration with the surrounding tissue. A microfluidic connector scheme was developed to promote compatibility with novel materials and implant applications. The connectors and an adhesive wax were printed on a scaffold via additive manufacturing processes. The low-temperature packaging process entailed bonding the connector to a polymer nanocomposite-based intracortical microfluidic probe using an adhesive wax. The robustness of the packaging was assessed by measuring the tensile and shear bond strengths of the connector-adhesive wax-polymer film interface. After soak testing for 4 weeks, the bond strength continued to exceed the force required to infuse fluids through the microfluidic channel. Further, the shear bond strength exceeded typical probe insertion forces by at least 10-fold. These results support the use of the connector and thermal bonding method as a viable option for chronic implant applications.

Determinants of Left Ventricular Hypertrophy and Diastolic Dysfunction in an HIV Clinical Cohort.

OBJECTIVE: The aim of this work was to investigate determinants of structural myocardial abnormalities in persons living with human immunodeficiency virus (PLWH). METHODS AND RESULTS: We reviewed archived transthoracic echocardiograms (TTEs) performed on PLWH at Duke University Medical Center from 2001 to 2012. The primary outcomes were presence of left ventricular hypertrophy (LVH) or diastolic dysfunction (DD). TTEs for 498 human immunodeficiency virus-infected persons were reviewed (median age 44 years, 38% female, 72% black, 34% with hypertension, 15% with diabetes). Among those with usable images, LVH was detected in 174 of 473 persons (37%) according to LV mass criteria and in 99 of 322 persons (31%) according to American Society of Echocardiography LV mass index criteria. Definite DD was detected in 18 of 224 persons (8%). LVH was more common in PLWH with a CD4 count ≤ 200 cells/mm3 proximal to TTE (adjusted OR 1.68, 95% CI 1.08-2.62), CD4 nadir ≤ 200 cells/mm3 (adjusted OR 1.63, 95% CI 1.04-2.54) and less common in persons with viral suppression (OR 0.46, 95% CI 0.27-0.80). Lower CD4 nadirs (P = .002) and proximal CD4 counts (P = .002) were also associated with DD. CONCLUSIONS: Persons with a history of advanced human immunodeficiency virus-associated immune suppression are at higher risk of LVH and DD than infected persons with preserved immune function.

Prognostic value of age adjusted segment involvement score as measured by coronary computed tomography: a potential marker of vascular age.

Extent of coronary atherosclerotic disease (CAD) burden on coronary computed tomography angiography (CCTA) as measured by segment involvement score (SIS) has a prognostic value. We sought to investigate the incremental prognostic value of 'age adjusted SIS' (aSIS), which may be a marker of premature atherosclerosis and vascular age. Consecutive patients were prospectively enrolled into the CONFIRM (Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicentre) multinational observational study. Patients were followed for the outcome of all-cause death. aSIS was calculated on CCTA for each patient, and its incremental prognostic value was evaluated. A total of 22,211 patients [mean age 58.5 ± 12.7 years, 55.8% male) with a median follow-up of 27.3 months (IQR 17.8, 35.4)] were identified. After adjustment for clinical factors and presence of obstructive CAD, higher aSIS was associated with increased death on multivariable analysis, with hazard ratio (HR) 2.40 (1.83-3.16, p < 0.001), C-statistic 0.723 (0.700-0.756), net reclassification improvement (NRI) 0.36 (0.26-0.47, p < 0.001), and relative integrated discrimination improvement (IDI) 0.33 (p = 0.009). aSIS had HR 3.48 (2.33-5.18, p < 0.001) for mortality in those without obstructive CAD, compared to HR 1.79 (1.25-2.58, p = 0.02) in those with obstructive CAD. In conclusion, aSIS has an incremental prognostic value to traditional risk factors and obstructive CAD, and may enhance CCTA risk stratification.

Machine learning for prediction of all-cause mortality in patients with suspected coronary artery disease: a 5-year multicentre prospective registry analysis.

AIMS: Traditional prognostic risk assessment in patients undergoing non-invasive imaging is based upon a limited selection of clinical and imaging findings. Machine learning (ML) can consider a greater number and complexity of variables. Therefore, we investigated the feasibility and accuracy of ML to predict 5-year all-cause mortality (ACM) in patients undergoing coronary computed tomographic angiography (CCTA), and compared the performance to existing clinical or CCTA metrics. METHODS AND RESULTS: The analysis included 10 030 patients with suspected coronary artery disease and 5-year follow-up from the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry. All patients underwent CCTA as their standard of care. Twenty-five clinical and 44 CCTA parameters were evaluated, including segment stenosis score (SSS), segment involvement score (SIS), modified Duke index (DI), number of segments with non-calcified, mixed or calcified plaques, age, sex, gender, standard cardiovascular risk factors, and Framingham risk score (FRS). Machine learning involved automated feature selection by information gain ranking, model building with a boosted ensemble algorithm, and 10-fold stratified cross-validation. Seven hundred and forty-five patients died during 5-year follow-up. Machine learning exhibited a higher area-under-curve compared with the FRS or CCTA severity scores alone (SSS, SIS, DI) for predicting all-cause mortality (ML: 0.79 vs. FRS: 0.61, SSS: 0.64, SIS: 0.64, DI: 0.62; P< 0.001). CONCLUSIONS: Machine learning combining clinical and CCTA data was found to predict 5-year ACM significantly better than existing clinical or CCTA metrics alone.

Do Surgeon Expectations Predict Clinically Important Improvements in WOMAC Scores After THA and TKA?

BACKGROUND: Failure of THA or TKA to meet a patient's expectations may result in patient disappointment and litigation. However, there is little evidence to suggest that surgeons can consistently anticipate which patients will benefit from those interventions. QUESTIONS/PURPOSES: To determine the ability of surgeons to identify, in advance of surgery, patients who will benefit from THA or TKA and those who will not, where 'benefit' is defined as a clinically important improvement in a validated patient-reported outcomes score. METHODS: In this prospective study, eight high-volume orthopaedic surgeons completed validated THA and TKA expectations questionnaires (score 0-100, 100 being the highest expectation) as part of preoperative assessment of all their patients scheduled for a THA or TKA and enrolled in the Hospital for Special Surgery institutional registry. Enrolled patients completed the WOMAC preoperatively and at 2 years. Successful outcomes were defined as achieving the minimum clinically important difference (MCID) in WOMAC pain and function subscales. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to evaluate the ability of surgeons' expectation scores to identify patients likely to achieve the MCID on the WOMAC scale. Analyses were run separately for patients having THA and TKA. We enrolled 259 patients undergoing THA and 247 undergoing TKA, of whom 77% (n = 200) and 77% (n = 191) completed followup surveys 2 years after their procedures, respectively. RESULTS: Surgeons' expectation scores effectively anticipated patients who would improve after THA, but they were no better than chance in identifying patients who would achieve the MCID on the WOMAC score 2 years after TKA. For patients having THA, the areas under the ROC curve were 0.67 (95% CI, 0.53-0.82; p = 0.02) and 0.74 (95% CI, 0.63-0.85; p < 0.01) for WOMAC function and pain outcomes, respectively, indicating good accuracy. Sensitivity and specificity were maximized on WOMAC pain and function scores (sensitivity = 0.69, specificity = 0.72, both for pain and function) at an expectations score of 83 or greater of 100. Surgeons' expectations were more accurate for patients who were men, who had a BMI less than 30 kg/m2, who had more than one comorbidity, and who were older than 65 years. For patients having TKA, surgeons' expectation scores were not better than chance for identifying those who would experience a clinically important improvement on the WOMAC scale (area under ROC curve: Function = 0.51, [95% CI, 0.42-0.61], p = 0.78; Pain = 0.51, [95% CI, 0.40-0.61], p = 0.92). CONCLUSIONS: Most patients having THA and TKA achieved the MCID improvement after surgery. However, the inability of surgeons' expectation scores to discriminate accurately between patients who benefit and those who do not among patients scheduled for THA who are young, with no comorbidities, and with elevated BMIs, and among all patients scheduled for TKA, calls for surgeons to spend more time with these patients to fully understand and address their needs and expectations. Using standardized assessment tools to compare surgeons' expectations and those of their patients may help focus the surgeon-patient discussion further, and address patients' expectations more effectively. LEVEL OF EVIDENCE: Level II, therapeutic study.

Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction.

AIMS: We aimed to determine the frequency of aortic valve surgery (AVR) with or without coronary artery bypass grafting (CABG), among patients with moderate/severe aortic stenosis (AS) and left ventricular systolic dysfunction (LVSD), and its relationship with survival. METHODS AND RESULTS: The Duke Echocardiographic Database (N = 132 804) was queried for patients with mean gradient ≥25 mmHg and/or peak velocity ≥3 m/s and LVSD (left ventricular ejection fraction ≤50%) from 1 January 1995-28 February 2014. For analyses purposes, AS was defined both by mean gradient and calculated aortic valve area (AVA) criteria. Time-dependent indicators of AVR in multivariable Cox models were used to assess the relationship of AVR and all-cause mortality. A total of 1634 patients had moderate (N = 1090, 67%) or severe (N = 544, 33%) AS by mean gradient criteria. Overall, 287 (26%) patients with moderate AS and 263 (48%) patients with severe AS underwent AVR within 5 years of the qualifying echo. There were 863 (53%) deaths observed up to 5 years following index echo. After multivariable adjustment in an inverse probability weighted regression model, AVR was associated with higher 5-year survival amongst patients with moderate AS and severe AS whether classified by AVA or mean gradient criteria. Over all, AVR ± CABG compared with medical therapy was associated with significantly lower mortality [hazard ratio, HR = 0.49 (0.38, 0.62), P < 0.0001]. Compared with CABG alone, CABG + AVR was associated with better survival [HR = 0.18 (0.12, 0.27), P < 0.0001]. CONCLUSIONS: In patients with moderate/severe AS and LVSD, mortality is substantial and amongst those selected for surgery, AVR with or without CABG is associated with higher survival. Research is required to understand factors contributing to current practice patterns and the possible utility of transcatheter approaches in this high-risk cohort.

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry) registry.

OBJECTIVE: We sought to examine the risk of mortality associated with nonobstructive coronary artery disease (CAD) and to determine the impact of baseline statin and aspirin use on mortality. APPROACH AND RESULTS: Coronary computed tomographic angiography permits direct visualization of nonobstructive CAD. To date, the prognostic implications of nonobstructive CAD and the potential benefit of directing therapy based on nonobstructive CAD have not been carefully examined. A total of 27 125 consecutive patients who underwent computed tomographic angiography (12 enrolling centers and 6 countries) were prospectively entered into the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry. Patients, without history of previous CAD or obstructive CAD, for whom baseline statin and aspirin use was available were analyzed. Each coronary segment was classified as normal or nonobstructive CAD (1%-49% stenosis). Patients were followed up for a median of 27.2 months for all-cause mortality. The study comprised 10 418 patients (5712 normal and 4706 with nonobstructive CAD). In multivariable analyses, patients with nonobstructive CAD had a 6% (95% confidence interval, 1%-12%) higher risk of mortality for each additional segment with nonobstructive plaque (P=0.021). Baseline statin use was associated with a reduced risk of mortality (hazard ratio, 0.44; 95% confidence interval, 0.28-0.68; P=0.0003), a benefit that was present for individuals with nonobstructive CAD (hazard ratio, 0.32; 95% confidence interval, 0.19-0.55; P<0.001) but not for those without plaque (hazard ratio, 0.66; 95% confidence interval, 0.30-1.43; P=0.287). When stratified by National Cholesterol Education Program/Adult Treatment Program III, no mortality benefit was observed in individuals without plaque. Aspirin use was not associated with mortality benefit, irrespective of the status of plaque. CONCLUSIONS: The presence and extent of nonobstructive CAD predicted mortality. Baseline statin therapy was associated with a significant reduction in mortality for individuals with nonobstructive CAD but not for individuals without CAD. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/. Unique identifier NCT01443637.

Current but not past smoking increases the risk of cardiac events: insights from coronary computed tomographic angiography.

AIMS: We evaluated coronary artery disease (CAD) extent, severity, and major adverse cardiac events (MACEs) in never, past, and current smokers undergoing coronary CT angiography (CCTA). METHODS AND RESULTS: We evaluated 9456 patients (57.1 ± 12.3 years, 55.5% male) without known CAD (1588 current smokers; 2183 past smokers who quit ≥3 months before CCTA; and 5685 never smokers). By risk-adjusted Cox proportional-hazards models, we related smoking status to MACE (all-cause death or non-fatal myocardial infarction). We further performed 1:1:1 propensity matching for 1000 in each group evaluate event risk among individuals with similar age, gender, CAD risk factors, and symptom presentation. During a mean follow-up of 2.8 ± 1.9 years, 297 MACE occurred. Compared with never smokers, current and past smokers had greater atherosclerotic burden including extent of plaque defined as segments with any plaque (2.1 ± 2.8 vs. 2.6 ± 3.2 vs. 3.1 ± 3.3, P < 0.0001) and prevalence of obstructive CAD [1-vessel disease (VD): 10.6% vs. 14.9% vs. 15.2%, P < 0.001; 2-VD: 4.4% vs. 6.1% vs. 6.2%, P = 0.001; 3-VD: 3.1% vs. 5.2% vs. 4.3%, P < 0.001]. Compared with never smokers, current smokers experienced higher MACE risk [hazard ratio (HR) 1.9, 95% confidence interval (CI) 1.4-2.6, P < 0.001], while past smokers did not (HR 1.2, 95% CI 0.8-1.6, P = 0.35). Among matched individuals, current smokers had higher MACE risk (HR 2.6, 95% CI 1.6-4.2, P < 0.001), while past smokers did not (HR 1.3, 95% CI 0.7-2.4, P = 0.39). Similar findings were observed for risk of all-cause death. CONCLUSION: Among patients without known CAD undergoing CCTA, current and past smokers had increased burden of atherosclerosis compared with never smokers; however, risk of MACE was heightened only in current smokers.

Incremental prognostic utility of coronary CT angiography for asymptomatic patients based upon extent and severity of coronary artery calcium: results from the COronary CT Angiography EvaluatioN For Clinical Outcomes InteRnational Multicenter (CONFIRM) study.

AIM: Prior evidence observed no predictive utility of coronary CT angiography (CCTA) over the coronary artery calcium score (CACS) and the Framingham risk score (FRS), among asymptomatic individuals. Whether the prognostic value of CCTA differs for asymptomatic patients, when stratified by CACS severity, remains unknown. METHODS AND RESULTS: From a 12-centre, 6-country observational registry, 3217 asymptomatic individuals without known coronary artery disease (CAD) underwent CACS and CCTA. Individuals were categorized by CACS as: 0-10, 11-100, 101-400, 401-1000, >1000. For CCTA analysis, the number of obstructive vessels-as defined by the per-patient presence of a ≥50% luminal stenosis-was used to grade the extent and severity of CAD. The incremental prognostic value of CCTA over and above FRS was measured by the likelihood ratio (LR) χ(2), C-statistic, and continuous net reclassification improvement (NRI) for prediction, discrimination, and reclassification of all-cause mortality and non-fatal myocardial infarction. During a median follow-up of 24 months (25th-75th percentile, 17-30 months), there were 58 composite end-points. The incremental value of CCTA over FRS was demonstrated in individuals with CACS >100 (LRχ(2), 25.34; increment in C-statistic, 0.24; NRI, 0.62, all P < 0.001), but not among those with CACS ≤100 (all P > 0.05). For subgroups with CACS >100, the utility of CCTA for predicting the study end-point was evident among individuals whose CACS ranged from 101 to 400; the observed predictive benefit attenuated with increasing CACS. CONCLUSION: Coronary CT angiography provides incremental prognostic utility for prediction of mortality and non-fatal myocardial infarction for asymptomatic individuals with moderately high CACS, but not for lower or higher CACS.

Diuretic response in acute heart failure-an analysis from ASCEND-HF.

BACKGROUND: Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. METHODS: Diuretic response, defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. RESULTS: Mean diuretic response was -0.42 kg/40 mg of furosemide (interquartile range -1.0, -0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response (P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. CONCLUSIONS: Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.

Cisterna chyli in autosomal dominant polycystic kidney disease.

PURPOSE: After observing prominent cisterna chyli in several patients with autosomal dominant polycystic kidney disease (ADPKD), we investigated the potential association of cistern chyli enlargement with ADPKD. MATERIALS AND METHODS: Retrospective, cross-sectional analysis of abdominal and pelvic MRI at 1.5 Tesla (T) in 70 ADPKD patients (male 44.3%, 20-83 years, median = 53 years) were compared with 70 age and gender matched control subjects without ADPKD, cirrhosis, or cholestasis. Cisterna chyli diameter was measured on axial single shot fast spin echo (SSFSE) images at the level of T12-L2 and evaluated by multivariable regression models with covariates including estimated glomerular filtration rate (eGFR), total kidney volume (TKV), renal cyst fraction (cyst volume/kidney volume), and liver volume. RESULTS: Subjects with ADPKD had larger median cisterna chyli diameter compared with those without ADPKD (6.1 mm versus 3.4 mm, P < 0.0001). The prevalence of cisterna chyli enlargement more than the median (3.4 mm), was greater in ADPKD than in controls (99% versus 51%, P < 0.0001). On univariate analysis, cisterna chyli diameter was inversely correlated with eGFR (r = -0.41; P < 0.0001) and directly correlated with TKV (r = 0.57; P < 0.0001), total renal cyst fraction (r = 0.61; P < 0.001), and liver volume (r = 0.17; P = 0.040). Multivariable linear regression modeling found a significant association of cisterna chyli diameter with ADPKD diagnosis (B = 2.14; 95% confidence interval [CI]: 0.05-4.23; P = 0.04). Logistic regression analysis confirmed the association of ADPKD with an enlarged cisterna chyli diameter (odds ratio = 68.4; 95%CI: 8.9-524, P < 0.0001). CONCLUSION: Enlarged cisterna chyli is highly prevalent in ADPKD patients but not in age and gender-matched controls.

Comparison of the prognostic value of regadenoson and adenosine myocardial perfusion imaging.

BACKGROUND: Regadenoson is now widely used in single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). However, the prognostic value of abnormal stress perfusion findings with regadenoson vs adenosine are unclear. The aim of this study was to evaluate the prognostic value of regadenoson SPECT and to compare it to that of adenosine SPECT. METHODS AND RESULTS: 3698 consecutive patients undergoing either adenosine or regadenoson SPECT were assessed at 1 year for the endpoints of cardiovascular death and a composite endpoint of cardiovascular death or MI. Weighted Cox proportional hazards regression modeling with the inverse probability weighted (IPW) estimators method adjusting to propensity for agent was used to account for differences in baseline characteristics. Patients undergoing adenosine SPECT MPI had a significantly higher prevalence of smoking history, diabetes, hypertension, and prior myocardial infarction (P < .05, all). At 1 year of follow-up, there were 154 cardiovascular deaths and 204 with the composite endpoint of cardiovascular death or MI. Using IPW adjustment to propensity for agent in a model with stress agent, summed stress score (SSS) remained a significant predictor of the composite endpoint of cardiovascular death or MI (HR 1.36 CI 1.28-1.46; P < .0001) as well as cardiovascular death (HR 1.38 CI 1.28-1.49; P < .0001). The interaction of SSS with agent was not significant. Similar findings were seen with summed difference score (SDS). CONCLUSIONS: SSS derived from either adenosine or regadenoson SPECT MPI is a significant predictor of events and provides incremental prognostic information beyond basic clinical variables. We have shown for the first time that use of regadenoson vs adenosine as stress agent does not modify the prognostic significance of SSS. Similar findings were seen with SDS.

Chorionic bump in pregnant patients and associated live birth rate: a systematic review and meta-analysis.

OBJECTIVES: A chorionic bump on first-trimester sonography has been considered a risk factor for nonviability in pregnant patients with this rare finding, although the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between a chorionic bump and nonviability. METHODS: A comprehensive literature search was performed. We included all studies except case reports. A meta-analysis was performed using a random-effects model. RESULTS: After screening 5 studies, 2 studies with a total of 67 patients met inclusion criteria. These were combined with a study (n = 52) from our institution. Overall, the live birth rate was 62% (74 of 119). Fifty-one chorionic bump pregnancies were otherwise normal (ie, pregnancies in which a gestational sac, a yolk sac, and an embryo with a heartbeat was seen at some point), and in this subset, the live birth rate was 83% (42 of 51). There was no significant relationship found between vaginal bleeding and live birth (P = .857); there was no significant difference in bump volume between live birth and no live birth (P = .198); and for the subset analysis of pooled odds ratios for the relationship between live birth and history of infertility, there was no significant relationship found (P = .186). CONCLUSIONS: A chorionic bump remains a risk factor for nonviability in pregnancy; however, if the pregnancy is otherwise normal, then most result in live birth.

Evaluation of computed tomography angiography plaque thickness measurements in high-grade carotid artery stenosis.

BACKGROUND AND PURPOSE: Increasing evidence suggests that carotid artery imaging can identify vulnerable plaque elements that increase stroke risk. We correlated recently proposed markers, soft and hard plaque thickness measurements on axial computed tomography angiography source images, with symptomatic disease status (ipsilateral stroke or transient ischemic attack) in high-grade carotid disease. METHODS: Soft plaque and hard plaque thickness were measured with a recently validated technique using computed tomography angiography source images in subjects with ≥70% extracranial carotid artery stenosis. Logistic regression analyses were used to assess the strength of association between soft and hard plaque thickness measurements and previous stroke or transient ischemic attack. Receiver operating characteristic analysis was also performed. RESULTS: Compared with asymptomatic subjects, those with symptomatic carotid disease had significantly larger soft plaque and total plaque thickness measurements and smaller hard plaque thickness measurements. Each 1-mm increase in soft plaque resulted in a 2.7 times greater odds of previous stroke or transient ischemic attack. Soft plaque thickness measurements provided excellent discrimination between symptomatic and asymptomatic disease, with receiver operating characteristic analysis showing an area under the curve of 0.90. A cutoff of 3.5-mm maximum soft plaque thickness provided a sensitivity of 81%, specificity of 83%, positive predictive value of 85%, and a negative predictive value of 78%. CONCLUSIONS: Increasing maximum soft plaque thickness measurements are strongly associated with symptomatic disease status in carotid artery stenosis. Prospective validation of these results may translate into a widely accessible stroke risk stratification tool in high-grade carotid artery atherosclerotic disease.

Left ventricular function and volume with coronary CT angiography improves risk stratification and identification of patients at risk for incident mortality: results from 7758 patients in the prospective multinational CONFIRM observational cohort study.

PURPOSE: To assess whether gradations of left ventricular (LV) ejection fraction (LVEF) and volumes measured with coronary computed tomography (CT) would augment risk stratification and discrimination for incident mortality. MATERIALS AND METHODS: This study was approved by the institutional review board, and informed consent was obtained when required. Subjects without known coronary artery disease (CAD) who underwent cardiac CT angiography with quantitative LV measurements were categorized according to LVEF (≥ 55%, 45%-54.9%, 35%-44.9%, or <35%). LV end-systolic volume (LVESV) and LV end-diastolic volume (LVEDV) were classified as normal (≥ 90 mL) or abnormal (≥ 200 mL). CAD extent and severity was categorized as none, nonobstructive, obstructive (≥ 50%), one-vessel, two-vessel, and three-vessel or left main disease. LVEF and volumes were assessed for risk prediction and discrimination of future mortality by using Cox hazards model and receiver operating characteristic curve analysis, respectively. RESULTS: During a follow-up of 2.0 years ± 0.9, 7758 patients (mean age, 58.5 years ± 13.0; 4220 male patients [54.4%]) were studied. At multivariable analysis, worsening LVEF was independently associated with mortality for moderately (hazard ratio = 3.14, P < .001) and severely (hazard ratio = 5.19, P < .001) abnormal ejection fraction. LVEF demonstrated improved discrimination for mortality (Az = 0.816) when compared with CAD risk factors alone (Az = 0.781) or CAD risk factors plus extent and severity. At multivariable analysis of a subgroup of 3706 individuals, abnormal LVEDV (hazard ratio = 4.02) and LVESV (hazard ratio = 6.46) helped predict mortality (P < .001). Similarly, LVESV and LVEDV demonstrated improved discrimination when compared with CAD risk factors or CAD extent and severity (P < .05). CONCLUSION: LV dysfunction and volumes measured with cardiac CT angiography augment risk prediction and discrimination for future mortality.

Sex-based prognostic implications of nonobstructive coronary artery disease: results from the international multicenter CONFIRM study.

PURPOSE: To determine the clinical outcomes of women and men with nonobstructive coronary artery disease ( CAD coronary artery disease ) with coronary computed tomographic (CT) angiography data in patients who were similar in terms of CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution. MATERIALS AND METHODS: Institutional review board approval was obtained for all participating sites, with either informed consent or waiver of informed consent. In a prospective international multicenter cohort study of 27 125 patients undergoing coronary CT angiography at 12 centers, 18 158 patients with no CAD coronary artery disease or nonobstructive (<50% stenosis) CAD coronary artery disease were examined. Men and women were propensity matched for age, CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution, which resulted in a final cohort of 11 462 subjects. Nonobstructive CAD coronary artery disease presence and extent were related to incident major adverse cardiovascular events ( MACE major adverse cardiovascular events ), which were inclusive of death and myocardial infarction and were estimated by using multivariable Cox proportional hazards models. RESULTS: At a mean follow-up ± standard deviation of 2.3 years ± 1.1, MACE major adverse cardiovascular events occurred in 164 patients (0.6% annual event rate). After matching, women and men experienced identical annualized rates of myocardial infarction (0.2% vs 0.2%, P = .72), death (0.5% vs 0.5%, P = .98), and MACE major adverse cardiovascular events (0.6% vs 0.6%, P = .94). In multivariable analysis, nonobstructive CAD coronary artery disease was associated with similarly increased MACE major adverse cardiovascular events for both women (hazard ratio: 1.96 [95% confidence interval { CI confidence interval }: 1.17, 3.28], P = .01) and men (hazard ratio: 1.77 [95% CI confidence interval : 1.07, 2.93], P = .03). CONCLUSION: When matched for age, CAD coronary artery disease risk factors, angina typicality, and nonobstructive CAD coronary artery disease extent, women and men experience comparable rates of incident mortality and myocardial infarction.