Cepharanthine Dry Powder Inhaler for the Treatment of Acute Lung Injury.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.

Physical activity trajectories and subsequent fall risk: ARIC Study.

To examine the impact of moderate to vigorous intensity physical activity (MVPA) trajectories during midlife and older adulthood with subsequent fall risk in later life. Cross-temporal analyses were conducted in 15,792 participants (27% black, 55% women) aged 45 to 64 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. MVPA was collected at Exams 1 (1987-89), 3 (1993-95) and 5 (2011-13) using the ARIC/Baecke questionnaire. Latent class growth analysis was used to identify the MVPA trajectory groups. Reported falls outcomes were collected in 2013-14, 2015-16, and 2016-17. Generalized Linear Models were used to estimate associations of baseline predictors with trajectory class membership, as well as associations of trajectory classes with any falling (adjusted incident relative risks, aIRR) and with number of falls (adjusted relative rates, aRR). Four primary trajectory classes emerged, reflecting longitudinal patterns of maintained high (48%), maintained low (22%), increasing (14%) and decreasing (15%) MVPA. After adjustment for covariates, the decreasing MVPA trajectory group had a 14% higher risk of reporting any falling compared to the maintained high MVPA group [aIRR = 1.14 (1.01, 1.28)]. When compared to the maintained high MVPA group, the maintained low and decreasing group had a 28% [aRR = 1.28 (1.14, 1.44)] and 27% [aRR = 1.27 (1.17, 1.38)] higher rate in the reported number of falls, respectively. Findings support public health campaigns targeting habitual MVPA or exercise for fall prevention and suggest that interventions should be initiated in midlife; a time when individuals may be more able and willing to change behavior.

EUS Needle Identification Comparison and Evaluation study (with videos).

BACKGROUND AND AIMS: EUS-guided FNA or biopsy sampling is widely practiced. Optimal sonographic visualization of the needle is critical for image-guided interventions. Of the several commercially available needles, bench-top testing and direct comparison of these needles have not been done to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. METHODS: Descriptive bench-top testing and comparison of 8 commonly used EUS-FNA needles (all size 22 gauge): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition (Cook Medical); ClearView (Conmed); EZ Shot 2 (Olympus); and BNX (Beacon Endoscopic), and 2 new prototype needles, SonoCoat (Medi-Globe), coated by echogenic polymers made by Encapson. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in GI US examination who were unfamiliar with EUS needle devices. RESULTS: There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, 1 prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (P < .01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%-75% worse, P < .001). CONCLUSIONS: All FNA needles have their inherent and different echogenicities, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity.

Small Brain Lesions and Incident Stroke and Mortality: A Cohort Study.

BACKGROUND: Although cerebral lesions 3 mm or larger on imaging are associated with incident stroke, lesions smaller than 3 mm are typically ignored. OBJECTIVE: To examine stroke risks associated with subclinical brain lesions (<3 mm only, ≥3 mm only, and both sizes) and white matter hyperintensities (WMHs). DESIGN: Community cohort from the ARIC (Atherosclerosis Risk in Communities) Study. SETTING: Two ARIC sites with magnetic resonance imaging (MRI) data from 1993 to 1995. PARTICIPANTS: 1884 adults aged 50 to 73 years with MRI, no prior stroke, and average follow-up of 14.5 years. MEASUREMENTS: Lesions on MRI (by size), WMH score (scale of 0 to 9), incident stroke, all-cause mortality, and stroke-related mortality. Hazard ratios (HRs) were estimated with proportional hazards models. RESULTS: Compared with no lesions, stroke risk tripled with lesions smaller than 3 mm only (HR, 3.47 [95% CI, 1.86 to 6.49]), doubled with lesions 3 mm or larger only (HR, 1.94 [CI, 1.22 to 3.07]), was 8-fold higher with lesions of both sizes (HR, 8.59 [CI, 4.69 to 15.73]), and doubled with a WMH score of at least 3 (HR, 2.14 [CI, 1.45 to 3.16]). Risk for stroke-related death tripled with lesions smaller than 3 mm only (HR, 3.05 [CI, 1.04 to 8.94]) and was 7 times higher with lesions of both sizes (HR, 6.97 [CI, 2.03 to 23.93]). LIMITATION: Few strokes (especially hemorrhagic) and few participants with lesions smaller than 3 mm only or lesions of both sizes. CONCLUSION: Very small cerebrovascular lesions may be associated with increased risks for stroke and death; presence of lesions smaller than 3 mm and 3 mm or larger may result in a particularly striking risk increase. Larger studies are needed to confirm findings and provide more precise estimates. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Feasibility study of utilizing ultraportable projectors for endoscopic video display (with videos).

BACKGROUND: Modern endoscopy requires video display. Recent miniaturized, ultraportable projectors are affordable, durable, and offer quality image display. OBJECTIVE: Explore feasibility of using ultraportable projectors in endoscopy. METHODS: Prospective bench-top comparison; clinical feasibility study. Masked comparison study of images displayed via 2 Samsung ultraportable light-emitting diode projectors (pocket-sized SP-HO3; pico projector SP-P410M) and 1 Microvision Showwx-II Laser pico projector. BENCH-TOP FEASIBILITY STUDY: Prerecorded endoscopic video was streamed via computer. CLINICAL COMPARISON STUDY: Live high-definition endoscopy video was simultaneously displayed through each processor onto a standard liquid crystal display monitor and projected onto a portable, pull-down projection screen. Endoscopists, endoscopy nurses, and technicians rated video images; ratings were analyzed by linear mixed-effects regression models with random intercepts. RESULTS: All projectors were easy to set up, adjust, focus, and operate, with no real-time lapse for any. Bench-top study outcomes: Samsung pico preferred to Laser pico, overall rating 1.5 units higher (95% confidence interval [CI] = 0.7-2.4), P < .001; Samsung pocket preferred to Laser pico, 3.3 units higher (95% CI = 2.4-4.1), P < .001; Samsung pocket preferred to Samsung pico, 1.7 units higher (95% CI = 0.9-2.5), P < .001. The clinical comparison study confirmed the Samsung pocket projector as best, with a higher overall rating of 2.3 units (95% CI = 1.6-3.0), P < .001, than Samsung pico. CONCLUSIONS: Low brightness currently limits pico projector use in clinical endoscopy. The pocket projector, with higher brightness levels (170 lumens), is clinically useful. Continued improvements to ultraportable projectors will supply a needed niche in endoscopy through portability, reduced cost, and equal or better image quality.

Quantitative proteome and lysine succinylome characterization of zinc chloride smoke-induced lung injury in mice.

The inhalation of zinc chloride (ZnCl2) smoke is one of common resources of lung injury, potentially resulting in severe pulmonary complications and even mortality. The influence of ZnCl2 smoke on lysine succinylation (Ksucc) in the lungs remains uncertain. In this study, we used a ZnCl2 smoke inhalation mouse model to perform global proteomic and lysine succinylome analyses. A total of 6781 Ksucc sites were identified in the lungs, with injured lungs demonstrating a reduction to approximately 2000 Ksucc sites, and 91 proteins exhibiting at least five differences in the number of Ksucc sites. Quantitative analysis revealed variations in expression of 384 proteins and 749 Ksucc sites. The analysis of protein-protein interactions was conducted for proteins displaying differential expression and differentially expressed lysine succinylation. Notably, proteins with altered Ksucc exhibited increased connectivity compared with that in differentially expressed proteins. Beyond metabolic pathways, these highly connected proteins were also involved in lung injury-associated pathological reactions, including processes such as focal adhesion, adherens junction, and complement and coagulation cascades. Collectively, our findings contribute to the understanding of the molecular mechanisms underlaying ZnCl2 smoke-induced lung injury with a specific emphasis on lysine succinylation. These findings could pave the way for targeted interventions and therapeutic strategies to mitigate severe pulmonary complications and mortality associated with such injuries in humans.

In situ forming hydrogel loaded with predatory bacteria treats drug-resistant corneal infection.

The development of potent bactericidal antibiotic alternatives is important to address the current antibiotic crisis. A representative example is the topical delivery of predatory Bdellovibrio bacteriovorus bacteria to treat ocular bacterial infection. However, the direct topical use of B. bacteriovorus suspensions has the problem of easy loss and inactivation. Here, a B. bacteriovorus in situ forming hydrogel (BIG) was constructed for the ocular delivery of B. bacteriovorus. BIGs, as a fluid in their primitive state, were temperature- and cation- dually sensitive, which was rapidly transformed into immobile gels in the ocular environment. BIGs not only kept the activity of B. bacteriovorus but also retained on the ocular surface for a long time. The biosafety of BIGs was good without HCEC cell toxicity and hemolysis. More importantly, BIGs highly inhibited the growth of drug-resistant Pseudomonas aeruginosa whether in vitro or in the infected rat eyes. The ocular infection was completely controlled by BIGs with no corneal ulcers and inflammations. This living bacteria gel is a promising medication for the local treatment of drug-resistant bacteria-induced ocular infection.

Predatory bacterial hydrogels for topical treatment of infected wounds.

Wound infection is becoming a considerable healthcare crisis due to the abuse of antibiotics and the substantial production of multidrug-resistant bacteria. Seawater immersion wounds usually become a mortal trouble because of the infection of Vibrio vulnificus. Bdellovibrio bacteriovorus, one kind of natural predatory bacteria, is recognized as a promising biological therapy against intractable bacteria. Here, we prepared a B. bacteriovorus-loaded polyvinyl alcohol/alginate hydrogel for the topical treatment of the seawater immersion wounds infected by V. vulnificus. The B. bacteriovorus-loaded hydrogel (BG) owned highly microporous structures with the mean pore size of 90 µm, improving the rapid release of B. bacteriovorus from BG when contacting the aqueous surroundings. BG showed high biosafety with no L929 cell toxicity or hemolysis. More importantly, BG exhibited excellent in vitro anti-V. vulnificus effect. The highly effective infected wound treatment effect of BG was evaluated on mouse models, revealing significant reduction of local V. vulnificus, accelerated wound contraction, and alleviated inflammation. Besides the high bacterial inhibition of BG, BG remarkably reduced inflammatory response, promoted collagen deposition, neovascularization and re-epithelization, contributing to wound healing. BG is a promising topical biological formulation against infected wounds.

Blood Pressure, Hypertension, and Antihypertensive Medication Use and Risk of Total and Fatal Prostate Cancer in Black and White Men in the Atherosclerosis Risk in Communities (ARIC) Study.

Black men are disproportionately burdened by hypertension and prostate cancer (PCa), and some cohorts suggest hypertension is associated with increased PCa risk. We investigated the association of hypertension and antihypertensive use with total (N = 889; 290 Black, 599 White) and fatal (N = 127; 42 Black, 85 White) PCa risk in 6658 (1578 Black, 5080 White) men in the Atherosclerosis Risk in Communities study. In adjusted Cox models, time-updated untreated stage 1 hypertension (systolic/diastolic blood pressure 130-139/80-89 mmHg) was associated with a higher risk of fatal PCa compared to untreated normal blood pressure (hazard ratio (HR) = 1.95; 95% confidence interval (CI) = 1.03-3.70). Compared to untreated normal/elevated blood pressure (combined given few events in those with untreated normal blood pressure), the association was significant in Black (HR = 3.35; 95% CI = 1.27-8.83), but not White (HR = 1.21; 95% CI = 0.58-2.55) men. Ever antihypertensive use was associated with a lower risk of fatal PCa compared to never use (HR = 0.52; 95% CI = 0.31-0.87), including short-term (< 10 years) and long-term (310 years) use (p-trend = 0.02) with similar inverse associations in Black and White men. Hypertension and antihypertensive use were not significantly associated with total PCa. The positive association of untreated stage 1 hypertension and fatal PCa warrants additional confirmation, especially in Black men, and characterization of the underlying mechanism.

Inhaled curcumin mesoporous polydopamine nanoparticles against radiation pneumonitis.

Radiation therapy is an effective method to kill cancer cells and shrink tumors using high-energy X-ray or γ-ray. Radiation pneumonitis (RP) is one of the most serious complications of radiation therapy for thoracic cancers, commonly leading to serious respiratory distress and poor prognosis. Here, we prepared curcumin-loaded mesoporous polydopamine nanoparticles (CMPN) for prevention and treatment of RP by pulmonary delivery. Mesoporous polydopamine nanoparticles (MPDA) were successfully synthesized with an emulsion-induced interface polymerization method and curcumin was loaded in MPDA via π‒π stacking and hydrogen bonding interaction. MPDA owned the uniform spherical morphology with numerous mesopores that disappeared after loading curcumin. More than 80% curcumin released from CMPN in 6 h and mesopores recovered. CMPN remarkably protected BEAS-2B cells from γ-ray radiation injury by inhibiting apoptosis. RP rat models were established after a single dose of 15 Gy 60Co γ-ray radiation was performed on the chest area. Effective therapy of RP was achieved by intratracheal administration of CMPN due to free radical scavenging and anti-oxidation ability, and reduced proinflammatory cytokines, high superoxide dismutase, decreased malondialdehyde, and alleviated lung tissue damages were observed. Inhaled CMPN paves a new avenue for the treatment of RP.

Pulmonary delivery of resveratrol-ß-cyclodextrin inclusion complexes for the prevention of zinc chloride smoke-induced acute lung injury.

Smoke bombs are often used in military/fire training, which can produce a large amount of zinc chloride (ZnCl2) smoke. Inhalation of ZnCl2 smoke usually causes acute lung injury (ALI) that would likely develop to acute respiratory distress syndrome (ARDS). However, there is no effective prevention or treatment strategy for the smoke-induced ALI. Resveratrol (RES) is a natural polyphenol with good anti-inflammatory and anti-apoptotic activities, but its low solubility, stability, and bioavailability restrict its clinical application. In this study, an inhalable RES formulation composed of RES-ß-cyclodextrin inclusion complexes (RES-ß-CD) was prepared for the prevention of ZnCl2 smoke-induced ALI. RES-ß-CD powders had a small mass median aerodynamic diameter of 3.61 µm and a high fine particle fraction of 38.84%, suitable for pulmonary inhalation. RES-ß-CD exhibited low BEAS-2B cytotoxicity. Pulmonary delivery of RES-ß-CD to mice remarkably prevented the smoke-induced ALI with downregulation of TNF-α, IL-1ß, STAT3, and GATA3, and upregulation of T-bet and Foxp3. RES-ß-CD protected the respiratory function, percutaneous oxygen saturation, physical activity, lung capillary integrity, and lung liquid balance, alleviating inflammation and apoptosis. Pulmonary delivery of the positive drug, budesonide (BUD), also alleviated the smoke-induced ALI by reduction of inflammation and cell apoptosis. RES-ß-CD exhibited the regulation of the Th1/Th2 and Treg/Th17 balances, while BUD did not show any effect on immune balances. In conclusion, pulmonary delivery of RES-ß-CD is a promising anti-inflammatory and anti-apoptosis strategy for the prevention of ZnCl2 smoke-induced ALI by direct lung drug distribution and regulation of immune balance.

Carotid Intima-Media Thickness and the Risk of Sudden Cardiac Death: The ARIC Study and the CHS.

Background Sudden cardiac death (SCD) is associated with severe coronary heart disease in the great majority of cases. Whether carotid intima-media thickness (C-IMT), a known surrogate marker of subclinical atherosclerosis, is associated with risk of SCD in a general population remains unknown. The objective of this study was to investigate the association between C-IMT and risk of SCD. Methods and Results We examined a total of 20 862 participants: 15 307 participants of the ARIC (Atherosclerosis Risk in Communities) study and 5555 participants of the CHS (Cardiovascular Health Study). C-IMT and common carotid artery intima-media thickness was measured at baseline by ultrasound. Presence of plaque was judged by trained readers. Over a median of 23.5 years of follow-up, 569 participants had SCD (1.81 cases per 1000 person-years) in the ARIC study. Mean C-IMT and common carotid artery intima-media thickness were associated with risk of SCD after adjustment for traditional risk factors and time-varying adjustors: hazard ratios (HRs) with 95% CIs for fourth versus first quartile were 1.64 (1.15-2.63) and 1.49 (1.05-2.11), respectively. In CHS, 302 participants developed SCD (4.64 cases per 1000 person-years) over 13.1 years. Maximum C-IMT was associated with risk of SCD after adjustment: HR (95% CI) for fourth versus first quartile was 1.75 (1.22-2.51). Presence of plaque was associated with 35% increased risk of SCD: HR (95% CI) of 1.37 (1.13-1.67) in the ARIC study and 1.32 (1.04-1.68) in CHS. Conclusions C-IMT was associated with risk of SCD in 2 biracial community-based cohorts. C-IMT may be used as a marker of SCD risk and potentially to initiate early therapeutic interventions to mitigate the risk.

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

BACKGROUND: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. METHODS: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. RESULTS: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease. INTERPRETATION: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia. FUNDING: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.

Long-Term Blood Pressure Level and Variability From Midlife to Later Life and Subsequent Cognitive Change: The ARIC Neurocognitive Study.

Background To understand how blood pressure ( BP ) from midlife and beyond is related to cognition in older age, a lifespan approach is needed. We assessed the associations of BP levels and variability from midlife on with subsequent cognitive change. Methods and Results The ARIC (Atherosclerosis Risk in Communities) Study participants underwent 4 clinic BP measurements (visit 1, 2, 3, and 4 BP s) between 1987 and 1998, and their mean levels and average real variability ( ARV ) were assessed as exposures. A global cognitive z score, estimated from the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test scores, was calculated at 1996 to 1998 (visit 4) and 2011 to 2013 (visit 5). Among 11 408 participants (mean age, 54 years; 56% women; 21% black race), mean systolic BP ( SBP )/diastolic BP ( DBP ) level was 123/72 mm Hg, and ARVSBP / ARVDBP was 11/7 mm Hg. With linear mixed models, 1- SD increases of ARVSBP (standardized regression coefficient [95% confidence interval], -0.03 [-0.04 to -0.01] points) and ARVDBP (standardized regression coefficient [95% confidence interval], -0.02 [-0.03 to -0.002] points; both P<0.05), but not mean SBP or DBP levels, were associated with lower global cognitive z scores at visit 4. In contrast, mean SBP (standardized regression coefficient [95% confidence interval], -0.04 [-0.06 to -0.02] points) or DBP (standardized regression coefficient [95% confidence interval], 0.04 [0.02-0.06] points; both P<0.001) level, but not ARVSBP or ARVDBP , was associated with change in global cognitive z scores from visits 4 to 5. Conclusions Greater visit-to-visit SBP or DBP variability from midlife on is modestly associated with lower cognitive function, whereas higher mean SBP and lower DBP levels from midlife to later life are modestly associated with cognitive decline in later life.

Diastolic wall strain is associated with incident heart failure in African Americans: Insights from the atherosclerosis risk in communities study.

BACKGROUND: Increased left ventricular (LV) myocardial stiffness may be associated with impaired LV hemodynamics and incident heart failure (HF). However, an indicator that estimates LV myocardial stiffness easily and non-invasively is lacking. The purpose of this study was to determine whether diastolic wall strain (DWS), an echocardiographic estimator of LV myocardial stiffness, is associated with incident HF in a middle-aged community-based cohort of African Americans. METHODS AND RESULTS: We investigated associations between DWS and incident HF among 1528 African Americans (mean age 58.5 years, 66% women) with preserved LV ejection fraction (EF ≥50%) and without a history of cardiovascular disease in the Atherosclerosis Risk in Communities Study. Participants with the smallest DWS quintile (more LV myocardial stiffness) had a higher LV mass index, higher relative wall thickness, and lower arterial compliance than those in the larger four DWS quintiles (p<0.01 for all). Over a mean follow-up of 15.6 years, there were 251 incident HF events (incidence rate: 10.9 per 1000 person-years). After adjustment for traditional risk factors and incident coronary artery disease, both continuous and categorical DWS were independently associated with incident HF (HR 1.21, 95%CI 1.04-1.41 for 0.1 decrease in continuous DWS, p=0.014, HR 1.40, 95%CI 1.05-1.87 for the smallest DWS quintile vs other combined quintiles, p=0.022). CONCLUSIONS: DWS was independently associated with an increased risk of incident HF in a community-based cohort of African Americans. DWS could be used as a qualitative estimator of LV myocardial stiffness.

Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.

Our previous experimental animal data suggest a beneficial effect of leptin on LV structure and function. We hypothesized that leptin levels are associated with lower LV mass and myocardial stiffness which are important risk factors for the development of heart failure with preserved ejection fraction (HFpEF). We evaluated 1172 blacks, in which the prevalence of HFpEF is quite high, with preserved LV ejection fraction (EF > 50%) from the Genetic Epidemiology Network of Arteriopathy Study (mean age 62.9 years, 72% women), a community-based study to identify genes influencing blood pressure and target organ damage due to hypertension. Associations between leptin levels and indices of LV structure and function were evaluated using generalized estimating equations accounting for clustering in siblings. LV myocardial stiffness was evaluated using diastolic wall strain (DWS) measured by echocardiography. Analyses were stratified by sex because leptin levels were three times higher in women than men (p < 0.001). After adjustment for confounders, higher leptin levels were associated with lower LV mass (coefficient for 1 s.d. increase of leptin level: -5.825 g, 95% CI: -9.755 to -1.895 g, P = 0.004) and higher DWS (lower LV stiffness) (coefficient for 1 s.d. increase of leptin level: 0.009, 95% CI: 0.002-0.015, P = 0.007) in women. There were no statistically significant associations in men. In women, there were interactions between leptin levels and body mass index quartiles on LV mass and stiffness (p < 0.05 for both). Higher leptin levels were associated with lower LV mass and stiffness in obese but not lean black women.

A SAS macro for the joint modeling of longitudinal outcomes and multiple competing risk dropouts.

BACKGROUND AND OBJECTIVES: The joint modeling of longitudinal and survival data to assess effects of multiple informative dropout mechanisms on longitudinal outcomes inference has received considerable attention during recent years; related statistical programs to apply these methods have been lacking. This paper provides a SAS macro implementation of a shared parameter model to accommodate the analysis of longitudinal outcomes in the presence of multiple competing survival/dropout events. METHODS: In this macro, we assumed that the associations between the survival and the longitudinal submodels are linked through a set of shared random effects. The submodel for the longitudinal outcome takes the form of a linear mixed effects model, with specifications for the random intercept and/or random slope. The survival submodel allows up to three different competing causes for dropout, each allowing either an exponential or Weibull parametric baseline hazard function. In addition, information criterion fit statistics AIC and BIC are provided to assist with parametric baseline hazard function selection. RESULTS: We illustrate the SAS Macro in a cognitive decline study sensitivity analysis using data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). In addition, we also conduct a simulation study to show that the joint model provides unbiased parameter estimates when informative dropout exists compared against separate model approach which assumes missing at random dropout mechanisms. CONCLUSIONS: We have presented a SAS macro to implement a shared parameter model for a longitudinal outcome and multiple cause-specific dropouts and made the macro code freely available for download.

Physical Activity Is Associated With Reduced Left Ventricular Mass in Obese and Hypertensive African Americans.

BACKGROUND: Physical activity (PA) has been associated with decreased left ventricular (LV) hypertrophy in previous studies. However, little is known about the relationship between PA and LV structure and factors which influence this relationship among African Americans. METHODS: We evaluated 1,300 African Americans with preserved LV ejection fraction (EF > 50%) from the Genetic Epidemiology Network of Arteriopathy (GENOA) Study (mean age 62.4 years, 73% women). PA index was calculated as 3 * heavy activity hours + 2 * moderate activity hours + slight activity hours/day. The relationship between PA index and LV structure was evaluated using generalized estimating equation. The association between PA index and LV mass index by age group, sex, body mass index (BMI), history of hypertension, diabetes or coronary heart disease, estimated glomerular filtration rate, and current smoking status were plotted. RESULTS: After adjustment for these factors, higher PA index was independently associated with lower LV mass index (P < 0.05). There were significant interactions between PA index and obesity (BMI ≥ 30) and history of hypertension on LV mass index (P for interaction <0.05, for both). Higher PA index was associated with lower LV mass index more in obese or hypertensive participants compared with nonobese or nonhypertensive participants. CONCLUSIONS: Higher PA index was associated with reduced LV hypertrophy in obese and hypertensive African Americans. Prospective studies aimed at assessing whether increasing PA prevents LV hypertrophy and potentially reduces the risk of heart failure in these at risk groups are warranted.

Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients.

INTRODUCTION: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. METHODS: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. RESULTS: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 (P=.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 (P=.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (P=.036), but a much attenuated remaining bulk tumor association, OR=1.46 (P=.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P=.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. CONCLUSIONS: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.

Enriching gene expression profiles will help personalize prostate cancer management for African-Americans: A perspective.

Prostate cancer (PCa) remains the most common form of cancer affecting men in the Western Hemisphere. Mortality rate is 130% higher among African-American men (AAM) than Caucasian-American men. As this trend is not new nor changing, there is an urgent need to identify markers with the ability to specifically distinguish aggressive PCa in the context of race. Gene expression patterns have been used as a tool to identify prognostic biomarkers for PCa to help reduce this disparity. Gene expression profiles reveal molecular mechanisms useful in understanding the biologic basis of tumorigenesis. Thus far, gene expression profiling analyses focused on race between AAM and Caucasian-American men (CAM) demonstrated distinct tumor microenvironments in the tumor-adjacent stroma and pathways associated with inflammation, lipid metabolism, and regulation of epithelial-to-mesenchymal transition. Additionally, we and others have established that hypoxia, another component of the tumor microenvironment, can been linked to malignant progression, metastasis, resistance to therapy, and poor clinical outcome in PCa. Gene expression panels, including distinct components related to the biology of PCa in AAM, may increase prognostic accuracy for this ethnic group. Furthermore, reference gene expression patterns, especially in the context of the emerging molecular taxonomy of PCa, would be buttressed by including more AAM in their development to consider the aspects of expression profiles differentially associated with race.