Search

Introduction: Non-fermenting gram-negative bacilli (NFGNB) infections have emerged as a serious health concern in ICUs. Multi-drug resistant (MDR) strains of NFGNB can evolve by acquiring resistance genes to at least one agent in three or more antibacterial categories. This study aimed to analyse the prevalence of NFGNB, the distribution of MDR strains, and antibiotic resistance trends of NFGNB in different ICUs of a tertiary care hospital over a period of five years., Materials and Methods: This retrospective study was conducted in a tertiary care teaching hospital in eastern India, including a total of 20,256 samples received from various ICUs over five years. Data retrieved from the Laboratory Information System (LIS) of the hospital, and repetitive isolates from the same patients, were excluded. All samples were processed according to standard microbiological protocols by automated systems. Data were entered into a Microsoft Excel spreadsheet (Microsoft® Corp., Redmond, WA, USA), analysed using Epi Info software, and presented using descriptive statistics. Chi-square and Fisher's exact tests (where appropriate) were used as tests of significance, with a p-value of <0.05 considered statistically significant., Results: A total of 18,032 culture-positive samples out of 20,256 samples showed growth of 18,659 bacteria. Out of these, 952 isolates were NFGNB. The prevalence of NFGNB was found to be 5.10% among all isolated bacteria. The predominant sources were respiratory samples (37.3%). Acinetobacter spp. emerged as the most prevalent NFGNB (46.5%), followed by Pseudomonas spp. (31%) and Burkholderia spp. (14.3%). Among the NFGNB isolates, 61.76% exhibited MDR, with the highest prevalence of MDR strains seen in Elizabethkingia spp. (94.7%). Among the most prevalent NFGNB, Acinetobacter spp., 64.8% were MDR strains. Trend analysis of antibiotic resistance patterns of Acinetobacter spp. indicated a substantial increase for trimethoprim-sulfamethoxazole by 18.5%, minocycline (44.4%), amikacin (20.4%), and ceftazidime (7.4%), whereas there was a reduced trend in resistance to carbapenems (6.5%), ciprofloxacin (4.7%), and cefepime (3.7%) over five years. In Pseudomonas spp., resistance to meropenem increased by 17.4%, and for ceftazidime (11.8%), amikacin (10.6%), and piperacillin-tazobactam (7.9%), whereas resistance to aztreonam diminished by 13.9%. Burkholderia spp. exhibited a 23.5% escalation in resistance to meropenem and ceftazidime (5.9%), while resistance to levofloxacin experienced a decrease of 30.2%., Conclusions: The study showed the prevalence of various NFGNB as 5.10% in ICU settings, with Acinetobacter spp. (46.5%) being the most common isolated bacteria. Notably, 61.76% of the isolates were MDR. Antibiotic trend analysis over five years showed increasing resistance of Acinetobacter spp. to trimethoprim-sulfamethoxazole, minocycline, and ceftazidime, with improved susceptibility for carbapenems, ciprofloxacin, and cefepime. Pseudomonas spp. showed increased susceptibility to aztreonam and rising resistance for meropenem, piperacillin-tazobactam, ceftazidime, and amikacin. In Burkholderia spp., there was increased susceptibility to levofloxacin and rising resistance to meropenem and ceftazidime. These findings focus on the need for vigilant antibiotic stewardship, with the adoption of appropriate infection prevention and control practices to restrict the emergence and spread of MDR NFGNB infections in ICU settings of hospitals., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dash et al.)

Background: Cardiac magnetic resonance is a useful clinical tool to identify late gadolinium enhancement in heart failure patients with implantable electronic devices. Identification of LGE in patients with CIED is limited by artifact, which can be improved with a wide band radiofrequency pulse sequence., Objective: The authors hypothesize that image quality of LGE images produced using wide-band pulse sequence in patients with devices is comparable to image quality produced using standard LGE sequences in patients without devices., Methods: Two independent readers reviewed LGE images of 16 patients with CIED and 7 patients without intracardiac devices to assess for image quality, device-related artifact, and presence of LGE using the American Society of Echocardiography/American Heart Association 17 segment model of the heart on a 4-point Likert scale. The mean and standard deviation for image quality and artifact rating were determined. Inter-observer reliability was determined by calculating Cohen's kappa coefficient. Statistical significance was determined by T -test as a p {less than or equal to} 0.05 with a 95% confidence interval., Results: All patients underwent CMR without any adverse events. Overall IQ of WB LGE images was significantly better in patients with devices compared to standard LGE in patients without devices ( p  = 0.001) with reduction in overall artifact rating ( p  = 0.05)., Conclusion: Our study suggests wide-band pulse sequence for LGE can be applied safely to heart failure patients with devices in detection of LV myocardial scar while maintaining image quality, reducing artifact, and following routine imaging protocol after intravenous gadolinium contrast administration., Competing Interests: Authors XM, MJ and AB were employed by company GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Shah, Krishnam, Ambale Venkatesh, Khan, Smith, Jones, Koon, Mao, Janich, Brau, Salerno, Dash, Chan and Yang.)

Floating Vegetated System (FVS) emerged as a green and sustainable technology, presenting a viable solution for treating heavy metals (HMs) contaminated water without disrupting the food web. Pistia stratiotes has been used in the design of FVS due to its abundance of aerenchyma tissues, which contribute to its ability to remain buoyant. FVS exhibited significant HMs removal efficiencies, with Pb top at average 84.4 %, followed by Zn (81.1 %), Cr (78.5 %), Cu (76.5 %) and Ni (73 %). Bio-concentration Factor (BCF) and Translocation Factor (TF) values evaluated the plant's adeptness in metal uptake. For plants treated with Cu, the highest post-treatment chlorophyll content of 9 ± 1 mg.ml -1 was observed while Zn induced plant shows the lowest content of 7.1 ± 0.4 mg.ml -1 . Using Box-Behnken Design (BBD), the system achieved 81.48 % Pb removal under optimized conditions such as initial Pb conc. of 9.25 mg. l -1 , HRT of 24.49 days and a water depth of 26.52 cm. ANOVA analysis highlighted the significant impact of all the factors such as initial HM conc., HRT and wastewater depth on FVS performance. Kinetic analysis estimated a closer observance to the zero-order model, supported by high determination coefficient (R 2 ) values. In conclusion, the FVS, as one of the most eco-friendly technologies, demonstrates higher potential for treating polluted water bodies, offering a sustainable remedy to global metal pollution challenges. Research on FVS for HMs removal is an area of ongoing interest and there are several potential future studies that could be pursued to further understand and optimize their effectiveness such as optimization of plant species, enhancement of plant-metal interactions, effects of environmental factors, economic feasibility studies, disposal of heavy metals accumulated plant, scale-up and application in real-world settings, etc., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Infected wounds pose a special challenge for management, with an increased risk of wound chronicity, systemic infection, and the emergence of antibiotic resistance. Silver nanoparticles have multimodal effects on bacteria clearance and wound healing. This study aimed to document the efficacy of a topical silver nanoparticle-based cream on bacteria clearance and wound healing in infected wounds compared to Mupirocin., Methods: This open-label parallel randomized clinical trial allocated 86 participants with infected wounds (culture-positive) into Kadermin, silver nanoparticle-based cream arm (n=43) and Mupirocin arm (n=43) and documented the swab culture on day 5 and wound healing at day 28, along with periodic wound status using the Bates-Jensen Wound Assessment Tool. Patients received oral/systemic antibiotics and other medications for underlying diseases. The intention-to-treat principle was adopted for data analysis using the chi-square and Student t tests to document the differences between groups according to variable characteristics., Results: All participants completed the follow-up. On day 5, wound bacteria clearance was observed in 86% and 65.1% of the participants in the Kadermin and Mupirocin arms, respectively (p=0.023). At day 28, complete wound healing was observed in 81.4% and 37.2% of the participants in the Kadermin and Mupirocin arms, respectively (p≤0.001). No local or systemic adverse event or local reaction was observed in any of the participants., Conclusion: Kadermin, the silver nanoparticle-based cream, has better efficacy in achieving faster wound bacteria clearance and healing in infected wounds compared to Mupirocin. This may have relevance for its use as an antibiotic-sparing agent in wound management., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Pathi et al.)

Background: Cardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting major cardiac adverse events recommend genetic testing for inherited cardiovascular conditions such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), hereditary amyloidosis, and familial hypercholesterolemia (FH); however, little is known about how consistently practitioners order genetic testing for these conditions in routine clinical practice. This study aimed to assess the adoption of guideline-directed genetic testing for patients diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH., Methods: This retrospective cohort study captured real-world evidence of genetic testing from ICD-9-CM and ICD-10-CM codes, procedure codes, and structured text fields of de-identified patient records in the Veradigm Health Insights Ambulatory EHR Research Database linked with insurance claims data. Data analysis was conducted using an automated electronic health record analysis engine. Patient records in the Veradigm database were sourced from more than 250,000 clinicians serving over 170 million patients in outpatient primary care and specialty practice settings in the United States and linked insurance claims data from public and private insurance providers. The primary outcome measure was evidence of genetic testing within six months of condition diagnosis., Results: Between January 1, 2017, and December 31, 2021, 224,641 patients were newly diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH and included in this study. Substantial genetic testing care gaps were identified. Only a small percentage of patients newly diagnosed with DCM (827/101,919; 0.8%), HCM (253/15,507; 1.6%), LQTS (650/56,539; 1.2%), hereditary amyloidosis (62/1,026; 6.0%), or FH (718/49,650; 1.5%) received genetic testing., Conclusions: Genetic testing is underutilized across multiple inherited cardiovascular conditions. This real-world data analysis provides insights into the delivery of genomic healthcare in the United States and suggests genetic testing guidelines are rarely followed in practice., Competing Interests: ML and SB were employed by and hold equity in the company Illumina, Inc. KB, AW, DL, and MN were employed by and hold equity in the company HealthPals, Inc. FR and RD were salaried consultants and equity holders of the company HealthPals, Inc., (© 2023 Longoni, Bhasin, Ward, Lee, Nisson, Bhatt, Rodriguez and Dash.)

Background: The COVID-19 pandemic accelerated adoption of telemedicine in cardiology clinics. Early in the pandemic, there were sociodemographic disparities in telemedicine use. It is unknown if these disparities persisted and whether they were associated with changes in the population of patients accessing care., Methods: We examined all adult cardiology visits at an academic and an affiliated community practice in Northern California from March 2019 to February 2020 (pre-COVID) and March 2020 to February 2021 (COVID). We compared patient sociodemographic characteristics between these periods. We used logistic regression to assess the association of patient/visit characteristics with visit modality (in-person vs telemedicine and video- vs phone-based telemedicine) during the COVID period., Results: There were 54,948 pre-COVID and 58,940 COVID visits. Telemedicine use increased from <1% to 70.7% of visits (49.7% video, 21.0% phone) during the COVID period. Patient sociodemographic characteristics were similar during both periods. In adjusted analyses, visits for patients from some sociodemographic groups were less likely to be delivered by telemedicine, and when delivered by telemedicine, were less likely to be delivered by video versus phone. The observed disparities in the use of video-based telemedicine were greatest for patients aged ≥80 years (vs age <60, OR 0.24, 95% CI 0.21, 0.28), Black patients (vs non-Hispanic White, OR 0.64, 95% CI 0.56, 0.74), patients with limited English proficiency (vs English proficient, OR 0.52, 95% CI 0.46-0.59), and those on Medicaid (vs privately insured, OR 0.47, 95% CI 0.41-0.54)., Conclusions: During the first year of the pandemic, the sociodemographic characteristics of patients receiving cardiovascular care remained stable, but the modality of care diverged across groups. There were differences in the use of telemedicine vs in-person care and most notably in the use of video- vs phone-based telemedicine. Future studies should examine barriers and outcomes in digital healthcare access across diverse patient groups., Competing Interests: Disclosures NK reports stock options from Gordy Health outside the submitted work. FR reports consulting fees from Novartis, Janssen, NovoNordisk, and HealthPals outside the submitted work. RD reports research funding from Bayer AG and consulting fees from HealthPals outside the submitted work. The remaining authors have nothing to disclose., (Published by Elsevier Inc.)

Medical literature shows that South Asians have approximately a 2-fold higher risk of atherosclerotic cardiovascular disease (CVD) compared with other populations. Given this high prevalence, clinical programs to promote cardiovascular health have emerged in the United States that are dedicated to clinical care for South Asian individuals. In this review, we have summarized the key characteristics of clinical programs in the U.S. dedicated to preventing and managing CVD in South Asian American patients. These clinical centers have many unique components in common that are catered to South Asian patient populations including ethnicity concordance of clinical providers, intensive cardiovascular screening protocols with laboratory studies and potentially genetic testing, dieticians and nutritionists who are familiar with South Asian-style dietary patterns, health coaches to support behavior change, community outreach programs, and involvement in clinical research to learn further about risk factors, prevention, and treatment of cardiovascular disease in South Asian populations. There are still many evidence and programmatic gaps left to uncover in the prevention, diagnosis, and management of CVD in South Asian. This review provides guidance for important features, barriers, and facilitators for future cardiovascular centers to develop in the United States where they can serve South Asian populations., Competing Interests: Disclosures R.D. and J.P. are involved in leadership of clinical programs described in this manuscript. The authors report no other disclosures or conflicts of interest

The Coronavirus Disease 2019 (COVID-19) pandemic curtailed clinical trial activity. Decentralized clinical trials (DCTs) can expand trial access and reduce exposure risk but their feasibility remains uncertain. We evaluated DCT feasibility for atrial fibrillation (AF) patients on oral anticoagulation (OAC). DeTAP (Decentralized Trial in Afib Patients, NCT04471623) was a 6-month, single-arm, 100% virtual study of 100 AF patients on OAC aged >55 years, recruited traditionally and through social media. Participants enrolled and participated virtually using a mobile application and remote blood pressure (BP) and six-lead electrocardiogram (ECG) sensors. Four engagement-based primary endpoints included changes in pre- versus end-of-study OAC adherence (OACA), and % completion of televisits, surveys, and ECG and BP measurements. Secondary endpoints included survey-based nuisance bleeding and patient feedback. 100 subjects (mean age 70 years, 44% women, 90% White) were recruited in 28 days (traditional: 6 pts; social media: 94 pts in 12 days with >300 waitlisted). Study engagement was high: 91% televisits, 85% surveys, and 99% ECG and 99% BP measurement completion. OACA was unchanged at 6 months (baseline: 97 ± 9%, 6 months: 96 ± 15%, p = 0.39). In patients with low baseline OACA (<90%), there was significant 6-month improvement (85 ± 16% to 96 ± 6%, p < 0.01). 86% of respondents (69/80) expressed willingness to continue in a longer trial. The DeTAP study demonstrated rapid recruitment, high engagement, and physiologic reporting via the integration of digital technologies and dedicated study coordination. These findings may inform DCT designs for future cardiovascular trials., (© 2022. The Author(s).)

Introduction: People with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) have increased morbidity and mortality risk. Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are recommended to slow kidney function decline in DKD. This representative, real-world data analysis of patients with T2DM was performed to detect onset of DKD and determine methods and timing of DKD diagnosis and time to initiation of ACEi/ARB therapy., Methods: Patients diagnosed with T2DM before January 1, 2016 who developed DKD between January 1, 2017 and June 30, 2019 were identified from a longitudinal ambulatory electronic health record (EHR) dataset (Veradigm Inc). Each record was analyzed using the CLinical INTelligence engine (CLINT™, HealthPals, Inc.) to identify delays and gaps in diagnosing DKD. DKD was diagnosed through two reduced estimated glomerular filtration rate (eGFR; < 60 mL/min/1.73 m 2 ) measurements at least 90 days apart, a single elevated urine albumin-to-creatinine ratio (UACR; > 30 mg/g) measurement, or ICD-9/10 diagnosis codes for DKD and/or albuminuria. Time to diagnose (TTD), time to treat (TTT), and diagnosis to treatment time were assessed., Results: Of 6,499,409 patients with T2DM before January 2016, 245,978 developed DKD between January 1, 2017 and June 30, 2019. In this DKD cohort, ca. 50% were first identified through EHR diagnosis and ca. 50% by UACR or eGFR lab-based diagnosis. In patients who had UACR/eGFR assessed, more than 90% exhibited DKD-level results on the first diagnostic test. Average TTD after eGFR labs was 2 years; average TTT with ACEi/ARB was 6-9 months after DKD lab evidence. The majority of patients who developed DKD received ACEi/ARB therapy 6-7 months after diagnosis., Conclusion: In a contemporary, large national cohort of patients with T2DM, progression to DKD was common but likely underrepresented. The low rate of DKD-screening labs, along with sizable delays in diagnosis of DKD and initiation of ACEi/ARB therapy, indicates that many patients who progress to DKD are not being properly treated., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: Malignant pleural effusion (MPE) portends a poor prognosis in non-small cell lung cancer (NSCLC). However, the yield of pleural fluid cytology as well as survival of patients with MPE associated with squamous cell carcinoma versus adenocarcinoma is not well understood. We conducted this study to assess the diagnostic yield of pleural cytology and survival of patients with NSCLC related MPE., Methods: We performed a single-center, retrospective analysis of patients with NSCLC related MPE between 2010 and 2017. Kaplan-Meier method was used to compare survival and Cox proportional hazards analysis to assess if squamous cell cytopathology was associated with mortality., Results: We identified 277 patients, 29 with squamous cell and 248 with adenocarcinoma MPE. Pleural fluid cytology from initial thoracentesis was diagnostic in 13.8% (4/29) patients with squamous cell and 80.2% (199/248) with adenocarcinoma (P<0.001). Cytology from second thoracentesis was diagnostic in 13.3% (2/15) patients with squamous cell carcinoma, compared to 37.5% (12/32) with adenocarcinoma (P=0.17). There was no statistically significant difference in the pleural biopsy yield from medical pleuroscopy or video-assisted thoracoscopic surgery (VATS) in the two groups. The median survival of patients with squamous cell MPE was 112 [interquartile range (IQR): 44-220] days versus 194 (IQR: 54-523) days in adenocarcinoma (Log-rank test P=0.04). Multivariate Cox proportional hazards analysis showed that squamous cell cytopathology was independent predictor of mortality (hazard ratio for death of 1.73, 95% CI: 1.1-2.6; P=0.01)., Conclusions: Pleural fluid cytology has a low diagnostic yield in squamous cell carcinoma MPE, and these patients have a poor survival compared to lung adenocarcinoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-123). The authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Integrating the health-care enterprise (IHE) is an international initiative to promote the use of standards to achieve interoperability among health information technology systems. The Pathology and Laboratory Medicine domain within IHE has brought together subject matter experts, electronic health record vendors, and digital imaging vendors, to initiate development of a series of digital pathology interoperability guidelines, called "integration profiles" within IHE. This effort begins with documentation of common use cases, followed by identification of available data and technology standards best utilized to achieve those use cases. An integration profile that describes the information flow and technology interactions is then published for trial use. Real world testing occurs in "connectathon" events, in which multiple vendors attempt to connect their products following the interoperability guidance parameters set forth in the profile. This paper describes the overarching set of integration profiles, one of which has been published, to support key digital pathology use cases., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pathology Informatics.)

Disturbingly high rates of consumption of surfactants in household and industries have led to mark them as emerging contaminants in the environment. In the present work, removal of sodium dodecyl sulfate (SDS), an anionic surfactant, using an industrial waste (dolochar) was explored. The adsorbent material was characterized with the help of Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Kinetic evaluation was performed using first, pseudo-first, second, and pseudo-second order models. Adsorption of SDS over dolochar was expressed best by pseudo-second order kinetic model with regression coefficient (R 2 ) of .99. Three input parameters including adsorbent dose (20-10 g/L), initial concentration (30-100 mg/L) of the surfactant, and contact time (2-60 min) were chosen for optimization using response surface methodology based on Box-Behnken design (BBD) approach. A total of 15 experiments were run to examine the effect of these variables on removal of SDS by dolochar in a multivariate system. A regression analysis indicated the experimental data fitted well to a quadratic polynomial model with coefficient of regression (R 2 ) as .99. ANOVA and lack-of-fit test depicted the precision and efficiency of the model. The optimized conditions for SDS removal were found to be adsorbent dose 16.62 g/L, contact time 40 min, and initial concentration 47 mg/L with removal efficiency as 98.91%. PRACTITIONER POINTS: Daily ablutions and use of personal care products introduce a number of surfactants and recalcitrant compounds into the environment. Adsorption is a handy and easy to operate treatment technique to remove graywater pollutants. Kinetic and statistical modeling may be recommended as one of the most prominent tools to understand the removal mechanism. Decentralized treatment of graywater using industrial wastes is recommended as sustainable solution in the developing nations., (© 2019 Water Environment Federation.)

Background: The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR., Methods: Lewis rats were induced to develop autoimmune myocarditis. CMR (3 T, GE Signa) was performed at the early- (day 14, n = 7) and the peak-phase (day 21, n = 8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24 h (6 h- & 24 h-FE-CMR) following the administration of ferumoxytol (300μmolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5 mmol/kg) on day 14 and 21. Healthy rats were used as control (n = 6)., Results: Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7 ± 15.5%; LGE: 8.7 ± 8.7%; both p = ns vs. controls). In contrast, 6 h-FE-CMR detected extensive myocardial signal loss (33.2 ± 15.0%, p = 0.02 vs. EGE and p < 0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4 ± 16.4% vs control: 66.2 ± 6.1%, p < 0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6 h-FE-CMR (41.6 ± 18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6 h R2* = 299 ± 112 s - 1 vs control: 125 ± 26 s - 1 , p < 0.01) and day 21 (564 ± 562 s - 1 , p < 0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27 ± 5 ms vs control: 16 ± 1 ms, p < 0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* (r = 0.86, p < 0.001)., Conclusions: FE-CMR acquired at 6 h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.

With increasing urbanization and industrialization, the scarcity of freshwater is becoming rampant. To counteract this, authorities all over the world are forced to consider the treatment and reuse of the wastewater produced by either industries or domestic units. After an extensive literature survey, vermifiltration coupled with/without macrophyte has been identified as one of the best sustainable, natural and eco-friendly technology for the treatment and reuse of wastewater. Till date, it has been successfully applied for treating domestic wastewater. However, the results from very limited industrial applications are also encouraging and proving its worth for industrial wastewater remediation. The present review on vermifiltration deals with the mechanisms involved and its current status for the remediation and reutilisation of the effluents generated from domestic and industrial premises. The review successfully identifies and explicitly discusses the mechanisms involved in the vermifiltration. The review exhaustively discusses the performance of vermifiltration and identifies the factors contributing to the performance of vermifiltration, which could be of help in designing of the field scale vermifilter based treatment plant. The review identifies the limitations associated with the vermifiltration and suggests possible alternatives, aimed to improve its performance and applicability. The aim of this review is to bring the attention of prospective researchers to study each and every aspect related to the vermifiltration so that it may be adopted as a reliable and dependable technology for the remediation of several industrial effluents meeting the concept of "Zero discharge"., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing., Methods: Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death., Results: We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020)., Conclusions: We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM., Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: RJHM is supported by the Arthur J E Child fellowship grant. GE Healthcare provides equipment research support to PCY, SH. AP was supported by the Breetwor Foundation. AS was supported by a research grant to EAA from MyoKardia. EAA is a consultant and receives researching funding with Myokardia. MTW has ownership interest and is a stockholder in Personalis and has ownership interest, research funding and consulting with MyoKardia. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Incorporating genetic variant data into the electronic health record (EHR) in discrete computable fashion has vexed the informatics community for years. Genetic sequence test results are typically communicated by the molecular laboratory and stored in the EHR as textual documents. Although text documents are useful for human readability and initial use, they are not conducive for data retrieval and reuse. As a result, clinicians often struggle to find historical gene sequence results on a series of oncology patients within the EHR that might influence the care of the current patient. Second, identification of patients with specific mutation results in the EHR who are now eligible for new and/or changing therapy is not easily accomplished. Third, the molecular laboratory is challenged to monitor its sequencing processes for nonrandom process variation and other quality metrics. A novel approach to address each of these issues is presented and demonstrated. The authors use standard Health Level 7 laboratory result message formats in conjunction with international standards, Systematized Nomenclature of Medicine Clinical Terms and Human Genome Variant Society nomenclature, to represent, communicate, and store discrete gene sequence data within the EHR in a scalable fashion. This information management plan enables the support of the clinician at the point of care, enhances population management, and facilitates audits for maintaining laboratory quality., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Manganese-enhanced MRI (MEMRI) detects viable cardiomyocytes based on the intracellular manganese uptake via L-type calcium-channels. This study aimed to quantify myocardial viability based on manganese uptake by viable myocardium in the infarct core (IC), peri-infarct region (PIR) and remote myocardium (RM) using T1 mapping before and after MEMRI and assess their association with cardiac function and arrhythmogenesis., Methods: Fifteen female swine had a 60-minute balloon ischemia-reperfusion injury in the LAD. MRI (Signa 3T, GE Healthcare) and electrophysiological study (EPS) were performed 4 weeks later. MEMRI and delayed gadolinium-enhanced MRI (DEMRI) were acquired on LV short axis. The DEMRI positive total infarct area was subdivided into the regions of MEMRI-negative non-viable IC and MEMRI-positive viable PIR. T1 mapping was performed to evaluate native T1, post-MEMRI T1, and delta R1 (R1 post -R1 pre , where R1 equals 1/T1) of each territory. Their correlation with LV function and EPS data was assessed., Results: PIR was characterized by intermediate native T1 (1530.5 ± 75.2 ms) compared to IC (1634.7 ± 88.4 ms, p = 0.001) and RM (1406.4 ± 37.9 ms, p < 0.0001). Lower post-MEMRI T1 of PIR (1136.3 ± 99.6 ms) than IC (1262.6 ± 126.8 ms, p = 0.005) and higher delta R1 (0.23 ± 0.08 s -1 ) of PIR than IC (0.18 ± 0.09 s -1 , p = 0.04) indicated higher myocardial manganese uptake of PIR compared to IC. Post-MEMRI T1 (r = -0.57, p = 0.02) and delta R1 (r = 0.51, p = 0.04) of PIR correlated significantly with LVEF., Conclusions: PIR is characterized by higher manganese uptake compared to the infarct core. In the subacute phase post-IR, PIR viability measured by post-MEMRI T1 correlates with cardiac function., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Pleural fluid can be used to assess targetable mutations in patients with lung adenocarcinoma. The primary objective of this study was to assess the yield of pleural fluid cytology for targetable oncogenic mutations (EGFR, KRAS, BRAF, ALK, and ROS1 gene rearrangements). We also assessed pleural fluid volume necessary for molecular testing., Methods: Retrospective review was performed of 134 consecutive patients with lung adenocarcinoma associated malignant pleural effusions. EGFR and KRAS testing was done using PCR amplification followed by DNA sequencing, or next generation sequencing in more recent cases that included BRAF assessment. Fluorescence in situ hybridization employing break-apart probes was used to test for ALK and ROS1 rearrangements., Results: Mutation analysis on pleural fluid cell-block was performed on 56 patients. It was adequate for complete analysis ordered including EGFR, KRAS, BRAF, ALK, and ROS1 rearrangements on 40 (71.4%) samples. For individual mutations, EGFR testing was possible in 38 of 49 (77.6%); KRAS 22 of 28 (78.6%); BRAF 10 of 13 (76.9%), ALK gene rearrangement 42 of 51 (82.4%) and ROS1 gene rearrangement in 21 of 28 (75%) pleural fluid specimens. The analysis was satisfactory in 13 of 19 (68.4%) samples with ≤100 mL versus 27 of 37 (72.9%) with >100 mL of fluid tested (P-value=0.7)., Conclusion: Genetic mutation analysis can be performed on malignant pleural effusions secondary to lung adenocarcinoma, independent of fluid volume.

Background: Diagnostic vitrectomy with flow cytometry immunophenotyping (FCI) is being increasingly used as part of screening for diagnostically challenging cases. We aim to evaluate the utility of combined cytopathology and FCI in diagnostic pars plana vitrectomy. We also aim to evaluate cytologic features that could potentially predict FCI outcomes. This study provides clearer indications for use of FCI in diagnostic vitrectomy., Methods: A case series of diagnostic pars plana vitrectomy specimens from 2010 to 2016 from a single institution was retrospectively evaluated. Associations between cytologic features and FCI were analyzed statistically., Results: Ninety-nine vitrectomy specimens (90 patients) were evaluated. Evaluation was diagnostic in 39 of 99 (39.4%) specimens. FCI was performed in 66 of 73 (90.4%) specimens collected for lymphoma indication, and 9 of those 66 FCIs (13.6%) demonstrated abnormal lymphocytes. FCI was performed in 10 of 26 (38.5%) specimens collected for non-lymphomatous indications; all 10 FCIs failed to demonstrate lymphocyte abnormality. The absence of large lymphocytes frequently demonstrated negative FCI (negative predictive value = 97.7%), and was the sole cytologic feature significantly associated with a negative FCI result [OR, 14.0; 95% CI, 1.65-635.6; P = .034]., Conclusions: Diagnostic vitrectomy with cytopathology evaluation is valuable, and concomitant FCI is useful to confirm intraocular lymphoma. However, the absence of large lymphocytes on cytologic examination is the single significant predictor of a negative FCI, and this finding should preclude the use of FCI., (© 2018 Wiley Periodicals, Inc.)

In the present research, an experiment was conducted with the objective of optimization of the role of earthworms in alleviating the bioclogging of a horizontal subsurface flow vermifilter (HSSFVF), caused due to the application of organics rich brewery wastewater. In this experiment, for the optimization of bioclogging of the vermifilters, the Box-Behnken Design (BBD) and response surface methodology (RSM) were involved. Hydraulic loading rate (HLR), influent COD and earthworm density (EWD) are the variables against which the bioclogging of the HSSFVF has been optimized. EWD of 9475 earthworms/m 3 , HLR of 1.84 m 3 /m 2 -d and influent COD of 3701 mg/L have been observed as the optimized values for the minimum bioclogging in the vermifiltration of brewery wastewater. At this optimum boundary conditions, the reduction in hydraulic conductivity was obtained as 1.49%, against the predicted value of 1.67% based upon the BBD model. The verification of the model against real brewery wastewater yielded insignificant error and thus very strongly portrays the suitability of the derived BBD model. The study indicates that the bioclogging from the vermifilters can be minimized, if the variables are optimized using the response surface methodology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The study was conducted with an aim to optimize the parameters involved in removing organics from brewery effluents using a newly developed horizontal subsurface flow vermifilter. It was also aimed at understanding the impact of hydraulic retention time (HRT) on the vermifiltration of brewery wastewater. With the help of Box-Behnken design (BBD) and response surface methodology, optimization of the COD removal from the vermifiltration was carried out. The parameters chosen for the optimization were hydraulic loading rate (HLR), organics strength and earthworm densities (EWDs). The model obtained from the response surface methodology (RSM) analysis was a quadratic polynomial model with R 2 value of 0.99. The optimal conditions for achieving maximum chemical oxygen demand (COD) removal were at influent COD concentration of 3542.22 mg/L, EWD of 9661.33 earthworms/m 3 and HLR of 1.84 m 3 /m 2 ·d. At the optimum conditions, COD removal of 94.99% was obtained against the predicted value of 95.85%. Verification of the model on real brewery wastewater also showed minimal error against the predicted COD removal. The COD, total nitrogen (TN) and total phosphorous (TP) removal at the HRT of 10.66 h were found to be 73.88%, 18.13% and 39.04%, respectively. Whereas, The COD, TN and TP removals at the HRT of 26.66 h were 96.24, 21.57 and 43.3%, respectively., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Global urbanization, exponential increase in population and sophisticated life style of the present generation are the major causes leading to a rapid increase in water demand in recent years. In order to nullify this rising water demand, it's high time to reuse domestic as well as industrial effluent after providing suitable chemical/biological treatment. Macrophyte filter incorporated with earthworm is identified as one of the most economic system for the treatment purpose in developing countries. However, very few literatures and technical information are available to scale up the design and its easy operation. This paper aims to develop a hybrid system and assess its performance for the purification of dairy wastewater. In the present study, two stage macrophyte assisted vermifilters (MAVFs) have been designed. The 1st stage encompassed a vertical flow (VF) unit, and the 2nd stage contained a horizontal flow (HF) unit. Both the units were inoculated with earthworm Eisenia fetida and were planted with Canna indica. Box-Behnken model was applied to design the system and study the effect of various parameters. It was observed that hybrid MAVF system removed a maximum of 83.2% COD and 57.3% TN at HLR 0.6 m/d and an active layer depth of 30 cm. Ammonification and nitrification typically occurred in the active layer (earthworm inoculated zone) of VF unit due to high activity of earthworms and its associated gut microbes, whereas HF unit facilitate denitrification process. Earthworm growth characteristics in the system were monitored, which is an imperative factor for the design of MAVF reactor. Kinetic modelling of 1st order, grau 2nd order and Stover-Kincannon model were performed and the Stover-Kincannon model showed high regression coefficient (COD, R 2 0.9961 and TN, R 2 0.9353) supporting its applicability as compared to the other models., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The present study was aimed at developing a mathematical COD removal index (CRI) based on the key variables of vermifiltration such as hydraulic retention time (HRT), organic concentration and earthworm density (EWD). In the maiden attempt of framing such an index, many experimental runs were conducted by varying the COD strength of the wastewater from 2.0-4.0 kg/m 3 , EWD and HLR were from 0 to 10,000 earthworms/m 3 and 1.8-4.5 m 3 /m 2 ·d, respectively. The sensitivity analysis of the developed CRI reveals that the EWD, bedding volume, concentration of organics and the flow applied to the vermifilter can immensely affect the model response. However, flow applied to the system is observed to be the most sensitive among other parameters incorporated in the model. In addition, from the sensitivity analysis, it was also revealed that the removal efficiencies were observed to increase with the increase in CRI values in the COD range of 0.2-6.0 kg/m 3 . In addition, the plot between the reported removals from literatures on vermifiltration of domestic wastewater and CRI values yielded an R 2 value of 0.76. Such a high correlation suggests that the developed CRI index can be applied for other wastewaters also. The results of this study indicate that the developed index can successfully be applied in determining and predicting organics removal from vermifiltration of wastewaters., (Copyright © 2018 Elsevier B.V. All rights reserved.)

With the scarcity of fresh water and rise in pollution load in the aquatic ecosystem over the globe, the domestic and industrial effluents need to be reused after suitable treatment. In an attempt to do so, soil biofilters have been identified as a treatment alternative that is suitable for application in developing countries. However, rapid development of clogging in the soil biofilters limits its applicability as an effective technology. This paper aims to understand the occurrence of clogging due to biofilms formation in and over the bedding of soil media. To address this, the organic loading rates (OLRs) were varied in the range of 2.25-11.25kgCOD/m 3 ·day to create different degree of clogging. Earthworms were inoculated into the soil bedding at the earthworm densities (EWDs) of 0, 5000 and 10,000earthworms/m 3 to study the effect of earthworms introduction on clogging. The degree of clogging was measured using clogging coefficient (CC), hydraulic conductivity and head loss. The study highlights the impact of earthworms on the removal performance and clogging of soil biofilter. For all earthworm densities, head loss and clogging coefficient increased and hydraulic conductivity decreased linearly with organic loading rate. Introduction of earthworms versus no earthworms resulted in lower head loss and clogging coefficient and higher hydraulic conductivity for all organic loading rates, while increasing EWD from 5000 to 10,000 had only marginal effects on all parameters. The study reveals that high organic loading rate activates higher number of microbial sites, in turn causing higher degree of clogging. However, the introduction of earthworms reduces the clogging rate significantly along with enhanced treatment performance. The outcome of this study indicates that incorporation of earthworms into the soil biofilter can reduce the degree of bio-clogging and might provide a highly sustainable, low cost and efficient treatment system for the developing countries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This work evaluates the performance efficiency of a newly developed single unit packed bed bioreactor for nutrient removal from domestic wastewater. The packing materials, including dolochar, and a mixture of waste organic solid substance, were immobilized with a simultaneous nitrifying, denitrifying and phosphate removing bacterial strain, Bacillus cereus GS-5 and packed in the bioreactor alternatively in multiple layers. The bioreactor was operated continuously for a period of 70 days using both synthetic and real domestic wastewater (NH 4 + -N 30-100 mg/L, NO 3 - -N 10-100 mg/L, PO 4 3- -P 5-20 mg/L and COD 250-1000 mg/L). The innovative single unit bioreactor exhibited simultaneous removal of NH 4 + -N (87.1-93.1%), NO 3 - -N (69.4-88.4%), PO 4 3- -P (84-100%), and even COD (69.8-92.1%), in a remarkable disparity to traditional distinct aerobic-anaerobic treatment systems. This work advocated for a promising and feasible application prospect of the developed single unit packed bed bioreactor in domestic wastewater treatment emphasizing on nutrient removal., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents.

Objectives: The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia., Background: Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage., Methods: Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology., Results: Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, -29 ± 19%, p = 0.041; 35°C: -17 ± 33%; 32°C: -1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease., Conclusions: Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A newly isolated GS-5 strain exhibiting heterotrophic nitrification, aerobic denitrification and denitrifying phosphorous removal was identified as Bacillus cereus GS-5 based on its phenotypic and phylogenetic characteristics. The isolate had exhibited efficient NH 4 + -N, NO 3 - -N, NO 2 - -N and PO 4 3- -P removal from nutrient spiked real domestic wastewater with average rates of 2.62, 2.69, 1.16 and 0.42mgL -1 h -1 , respectively under aerobic condition. Metabolic inhibitor based mass balance analysis indicated that dinitrogen gas (41%), intracellular nitrogen (29%) and intracellular phosphorous (60%) were the major fates of the initial NH 4 + -N and PO 4 3- -P. The successfully expression of hydroxylamine oxidase (hao), nitrate reductase (nar), nitrite reductase (nir) and poly phosphate kinase (ppk) enzyme in the cell free extracts and PCR amplification of nar, nir and ppk genes in the isolated strain provided further evidences for the nutrient removal possibility. A possible pathway of for nitrogen removal by GS-5 is suggested., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

With global population explosion, the available water resources are slowly being polluted due to the excessive human interference. To encounter this, it is the need of this hour to find out sustainable pollution remediating technologies to meet the stringent discharge standards for domestic as well as industrial wastewaters. In addition, those techniques should have the capabilities for effective implementation even in developing countries. Based on the available literatures, one such technique, named vermifilter, has been identified which takes care of almost all the sustainable and economical criteria for its effective implementation even in developing countries. The aim of this meta-analysis is to provide a comprehensive review on assessment mechanisms involved, factors affecting the process and performance of vermifiltration under different scenarios. The present review envisages the current state of the knowledge regarding physical, chemical and biological aspects related to the treatment mechanisms and effective functioning of earthworms. This review has also proposed several suggestive plans on its application at any proposed site., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to establish the criteria defining an anticipatory positive test for bladder cancer., Methods: We reviewed all patients at our institution who underwent urine cytology or UroVysion fluorescence in situ hybridization (FISH) and cystoscopy from 2003 to 2012. Test performance and cancer anticipation was assessed using generalized linear mixed models, mixed-effects proportional hazards models, and cumulative incidence curves using tests performed within 30 days of each other as well as within a lag time of 1 year., Results: Overall, 6729 urine tests (4729 cytology and 2040 UroVysion FISH) were paired with gold-standard cystoscopies. Sensitivity and specificity were 63 and 41% for cytology, and 37 and 84% for UroVysion FISH, respectively. A 1-year lag time allowed for cancer anticipation and neither test improved. Among patients with positive cytology and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.83; 76% of these patients developed a tumor within 1 year. Similarly, among patients with a positive FISH and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.56; 40% of these patients developed a tumor within 1 year., Conclusions: Urine-based tests for bladder cancer are frequently falsely positive. With further follow-up time, some of these false positive tests are vindicated as true (anticipatory) positive tests, although many will remain false positives. We developed statistical criteria to determine if a test anticipates future cancers or not.

Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies., Competing Interests: UCSF owns a patent with PCS as inventor for use of A61603 in heart failure, and PCS is involved in a company to pursue this. The indicated patent owned by UCSF is "Method of treatment using alpha-1-adrenergic agonist compounds" (inventor Paul C. Simpson) (allowed #8324178, 2009). This patent has not resulted in any company, product, employment, etc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model., Methods: 51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5μg/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9., Results: A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9±3.2% to 23.1±1.7%* vs. 23.5±1.7% to 16.9±2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri-infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri-infarct region (16.5±3.1% vs. 8.1±1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found., Conclusions: A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Spectrum effects refer to the phenomenon that test performance varies across subgroups of a population. When spectrum effects occur during diagnostic testing for cancer, difficult patient misdiagnoses can occur. Our objective was to evaluate the effect of test indication, age, gender, race, and smoking status on the performance characteristics of two commonly used diagnostic tests for bladder cancer, urine cytology and fluorescence in situ hybridization (FISH)., Methods: We assessed all subjects who underwent cystoscopy, cytology, and FISH at our institution from 2003 to 2012. The standard diagnostic test performance metrics were calculated using marginal models to account for clustered/repeated measures within subjects. We calculated test performance for the overall cohort by test indication as well as by key patient variables: age, gender, race, and smoking status., Results: A total of 4023 cystoscopy-cytology pairs and 1696 FISH-cystoscopy pairs were included in the analysis. In both FISH and cytology, increasing age, male gender, and history of smoking were associated with increased sensitivity and decreased specificity. FISH performance was most impacted by age, with an increase in sensitivity from 17 % at age 40 to 49 % at age 80. The same was true of cytology, with an increase in sensitivity from 50 % at age 40 to 67 % at age 80. Sensitivity of FISH was higher for a previous diagnosis of bladder cancer (46 %) than for hematuria (26 %). Test indication had no impact on the performance of cytology and race had no significant impact on the performance of either test., Conclusions: The diagnostic performance of urine cytology and FISH vary significantly according to the patient demographic in which they were tested. Hence, the reporting of spectrum effects in diagnostic tests should become part of standard practice. Patient-related factors must contextualize the clinicians' interpretation of test results and their decision-making.

Inflammation plays a significant role in a wide range of cardiovascular diseases (CVDs). The numerous implications of inflammation in all steps of CVDs, including initiation, progression and complications, have prompted the emergence of noninvasive imaging modalities as diagnostic, prognostic and monitoring tools. In this review, we first synthesize the existing evidence on the role of inflammation in vascular and cardiac diseases, in order to identify the main targets used in noninvasive imaging. We chose to focus on positron emission tomographic (PET) and magnetic resonance imaging (MRI) studies, which offer the greatest potential of translation and clinical application. We detail the main preclinical and clinical studies in the following CVDs: coronary and vascular atherosclerosis, abdominal aortic aneurysms, myocardial infarction, myocarditis, and acute heart transplant rejection. We highlight the potential complementary roles of these imaging modalities, which are currently being studied in the emerging technology of PET/MRI. Finally, we provide a perspective on innovations and future applications of noninvasive imaging of cardiovascular inflammation. (Circ J 2016; 80: 1269-1277).

Background: A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI-DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model., Methods and Results: Dual contrast MEMRI-DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs)., Conclusion: The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI-DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

Background: The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts., Methods and Results: Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05)., Conclusions: The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated., Methods: Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared., Results: The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001)., Conclusions: Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal., (Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Context: Biospecimens must have appropriate clinical annotation (data) to ensure optimal quality for both patient care and research. Clinical preanalytic variables are the focus of this study., Objective: To define the essential preanalytic variables (data fields) that should be attached to every collected biospecimen and to provide a complete list of such variables, along with their relative importance, which can vary, depending on downstream use, institutional needs, and information technology capabilities., Design: The College of American Pathologists Diagnostic Intelligence and Health Information Technology Committee sponsored a Biorepository Working Group to develop a ranked list of the preanalytic variables for annotating biospecimens. Members of the working group were experts in anatomic, clinical, and molecular pathology; biobanking; medical informatics; and accreditation. Several members had experience with federal government programs, such as the National Cancer Institute's Biospecimens and Biorepository Branch and the National Cancer Institute's Community Cancer Center Program. Potential preanalytic variables were identified and ranked along with available supporting evidence, definitions, and potential negative effects if the variable was not attached to the biospecimen. Additional national and international stakeholders reviewed the draft manuscript., Results: The ranked listing of 170 preanalytic variables produced can be used as a guide for site-specific implementation into patient care and/or research biorepository processes. Conclusions.-In our collective experience, it is often difficult to choose which of the many preanalytic variables to attach to any specific set of biospecimens used for patient care and/or research. The provided ranked list should aid in the selection of preanalytic variables for a given biospecimen collection.

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.

Background: Patients with a myocardial bridge (MB) and no significant obstructive coronary artery disease (CAD) may experience angina presumably from ischemia, but noninvasive assessment has been limited and the underlying mechanism poorly understood. This study seeks to correlate a novel exercise echocardiography (EE) finding for MBs with invasive structural and hemodynamic measurements., Methods and Results: Eighteen patients with angina and an EE pattern of focal end-systolic to early-diastolic buckling in the septum with apical sparing were prospectively enrolled for invasive assessment. This included coronary angiography, left anterior descending artery (LAD) intravascular ultrasound (IVUS), and intracoronary pressure and Doppler measurements at rest and during dobutamine stress. All patients were found to have an LAD MB on IVUS. The ratios of diastolic intracoronary pressure divided by aortic pressure at rest (Pd/Pa) and during dobutamine stress (diastolic fractional flow reserve [dFFR]) and peak Doppler flow velocity recordings at rest and with stress were successfully performed in 14 patients. All had abnormal dFFR (≤0.75) at stress within the bridge, distally or in both positions, and on average showed a more than doubling in peak Doppler flow velocity inside the MB at stress. Seventy-five percent of patients had normalization of dFFR distal to the MB, with partial pressure recovery and a decrease in peak Doppler flow velocity., Conclusions: A distinctive septal wall motion abnormality with apical sparing on EE is associated with a documented MB by IVUS and a decreased dFFR. We posit that the septal wall motion abnormality on EE is due to dynamic ischemia local to the compressed segment of the LAD from the increase in velocity and decrease in perfusion pressure, consistent with the Venturi effect.

Background: Macrophages are critical contributors to atherosclerosis. Single-walled carbon nanotubes (SWNTs) show promising properties for cellular imaging and thermal therapy, which may have application to vascular macrophages., Methods and Results: In vitro uptake and photothermal destruction of mouse macrophage cells (RAW264.7) were performed with SWNTs (14.7 nmol/L) exposed to an 808-nm light source. SWNTs were taken up by 94 ± 6% of macrophages, and light exposure induced 93 ± 3% cell death. In vivo vascular macrophage uptake and ablation were then investigated in carotid-ligated FVB mice (n=33) after induction of hyperlipidemia and diabetes. Two weeks postligation, near-infrared fluorescence (NIRF) carotid imaging (n=12) was performed with SWNT-Cy5.5 (8 nmol of Cy5.5) given via the tail vein. Photothermal heating and macrophage apoptosis were evaluated on freshly excised carotid arteries (n=21). NIRF of SWNTs showed higher signal intensity in ligated carotids compared with sham, confirmed by both in situ and ex vivo NIRF imaging (P<0.05, ligation versus sham). Immunofluorescence staining showed colocalization of SWNT-Cy5.5 and macrophages in atherosclerotic lesions. Light (808 nm) exposure of freshly excised carotids showed heating and induction of macrophage apoptosis in ligated left carotid arteries with SWNTs, but not in control groups without SWNTs or without light exposure., Conclusions: Carbon nanotubes accumulate in atherosclerotic macrophages in vivo and provide a multifunctional platform for imaging and photothermal therapy of vascular inflammation.

Benign papillary lesions of the breast include papilloma and papillomatosis. A retrospective analysis of patients with a papillary breast lesion diagnosed between October 1992 and December 2009 was performed. Patients were excluded if they had a previous or concurrent diagnosis of invasive or in situ cancer or less than 6 months of follow-up. The Kaplan-Meier method was used to determine the risk of developing subsequent malignancy. The log rank test was used to compare groups of patients. Median follow-up for the 167 patients included in the study was 4.6 years. Fifty-one patients had a papillary lesion with atypia and 116 patients had a papillary lesion without atypia. Patients with a papillary lesion with atypia were more likely to develop invasive or in situ breast cancer with a 5 year risk of 13.0% versus 4.6% in patients with no atypia (p = 0.03)., (© 2012 Wiley Periodicals, Inc.)

Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+)) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+). Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+)., (Copyright © 2011 Wiley Periodicals, Inc.)