Search

Farm and crop diversification is an important farm business strategy from the viewpoint of avoiding uncertain crop failures and loss of income, intensive cultivation of a single crop such as rice and wheat, indiscriminate use of chemical inputs and ensuring farm sustainability. However, the question remains whether farm diversification helps farmers reduce the extent of input use and cost with an improvement in farm income and welfare. Therefore, the present study aimed at examining the impact of crop diversification under the paddy-dominated farming system in India using national level farm household data pertaining to the year 2012–2013. We used propensity score matching technique for estimating the actual impact of crop diversification on the farm income and input use pattern. The study results show that crop diversification has significantly increased yield of paddy, farm income and reduced cost on labour, machinery and irrigation under paddy-dominated cropping system.

Cost of Cultivation of Principal Crops (CCPC) data from 2014–15 to 2016–17 was collected and converted as a panel data to estimate the technical and allocative inefficiency indexes and its impact on input demand and cost of sugarcane production. The present study adopted the primal system approach, with the Cobb-Douglas production function and the first-order conditions of cost minimization. Returns to scale value confirmed that there is a vast scope to increase India's sugarcane yield. Results also revealed that fertilizer is the most under-utilized whereas setts and irrigation are the most over-utilized resources in Indian sugarcane production. Machinery usage was under-utilized in Karnataka, Tamil Nadu, and Uttar Pradesh. The technical inefficiency in sugarcane production reduces the input demand of labour, setts, fertilizer, irrigation, and machinery by 2.70 percent, 4.90 percent, 3.30 percent, 3.50 percent, and 7.60 percent respectively. Technical-and-allocative inefficiency collectively increases the cost of sugarcane production by 46.80 percent in Andhra Pradesh, followed by 44.30 percent in Maharashtra, 35.90 percent in Tamil Nadu, 27.10 percent in Uttar Pradesh, 24.70 percent in Karnataka, and 23 percent in Uttarakhand. It confirms that existing sugarcane yield of India can be attained with 33.60 percent lesser than the existing production cost. These results suggest establishing rural-based agricultural machinery custom hiring centres, proper irrigation structures, and single bud chips as a planting material would increase the sugarcane production as well as reduce the cost of cultivation.

> I am a member of a vast team, > > Yet I work alone. > I feel valued by many, > > Yet I am undervalued by a key few. > I own, manage and work independently, > > Yet I am accountable to everyone. > I must offer judgement, …

Introduction Pharmacovigilance is essential to monitoring the safety profiles of authorized medicines. Compared with small-molecule drugs, biological drugs are more complex, more susceptible to structural variability due to manufacturing processes, and have the potential to induce immune-related reactions, underscoring the importance of safety monitoring for these products. Although highly similar to reference products, biosimilars are not expected to be structurally identical. For these reasons, proper reporting of potential adverse drug reactions (ADRs) using distinguishable names and batch numbers is essential for accurate tracing of all biological drugs. To address the need for robust pharmacovigilance, the European Parliament and Council of the European Union provided legislation regarding pharmacovigilance of biologics in 2010. Areas covered This narrative review examines the current state of pharmacovigilance for biologics in the European Union (EU) and discusses relevant information on pharmacovigilance of biosimilars, the current EU pharmacovigilance system, and areas that could be improved. Expert opinion Although steps have been taken to improve pharmacovigilance of biologics in the EU, several enhancements can still be made, including additional training for healthcare professionals on ADR reporting, the use of 2D barcodes that enhance traceability, and an open discussion of potentially missed opportunities in the pharmacovigilance of biosimilars.

The sympathetic nervous system plays a crucial role in blood pressure regulation and the development of hypertension.

In September 2016, the Food and Drug Administration (FDA) published a draft guidance for industry,For the 3-year period, 2015-2017, which included a full year of FDA approvals both before and after the issuance of the draft guidance, publicly available FDA reviews were analyzed for all 113 approved products using the criteria outlined in the guidance.Of the 113 products approved, 5 required a REMS. The most cited reasons for not requiring a REMS for the remaining 108 drugs were that risks could be managed via professional labeling (87%), physicians (primarily specialists) were familiar with the management of the risks (76%), the risk profile was similar to other non-REMS marketed products (45%), products were used in a controlled setting (inpatient, infusion center) (30%), and/or safety concerns would be further evaluated by a postmarket study (14%).A review of Agency risk evaluations indicate that whether physicians are sufficiently familiar with and capable of managing a risk and that the health care setting where the product is administered is conducive to such management are leading factors in determining whether or not to require a REMS.

In 2015, five or more biosimilars may be approved in the USA. Because no two biologic medicines are identical, postapproval safety monitoring will be critical to detect potential differences in safety signals between a biosimilar, its reference product, and other biosimilars. Postapproval safety monitoring in the USA uses two signal detection systems: spontaneous reporting systems (SRSs) and active surveillance (AS) systems. Both depend on accurate identification of the specific product(s) dispensed or administered to patients, which may be compromised when products from multiple manufacturers share common drug nomenclature or coding. Product identification can present challenges across different healthcare settings, including inpatient and ambulatory care. Common oral-dosage drugs are predominantly dispensed directly to patients by pharmacists, whereas most injectable drugs, including biologics, are administered to patients by healthcare professionals in outpatient clinics or hospitals. Thus, the effectiveness of SRS and AS mechanisms in both pharmacy and medical channels must be given greater consideration as biotechnology matures. In this article, we describe these systems and their limitations. We identify challenges and opportunities for product-specific safety surveillance of biologics in both the pharmacy and medical settings and provide recommendations to improve biologic safety surveillance under the current and future systems envisioned in the Drug Quality and Security Act. As biosimilars are integrated into existing pharmacovigilance systems, distinguishable nonproprietary names and codes for all biologics, as well as other opportunities to improve traceability (e.g., increased use of barcodes), must be considered to ensure patient safety and confidence in this new class of drugs.

As of 2014, the US FDA was considering policy options to promote accurate attribution of adverse events for biosimilars. In order to assess the identification and traceability of biologics from multiple sources, Tufts University's Center for the Study of Drug Development conducted a study reviewing the current FDA Adverse Event Reporting System (FAERS) for reports related to insulin and growth hormone products.For this study, all primary suspect reports that were received by FAERS for human growth hormone (hGH) and human insulin between the fourth quarter of 2005 and the third quarter of 2013 were extracted and analyzed.The rates of "accurate" brand (ie, identifiable) drug names were generally high, with a higher incidence for hGH drugs than for insulin drugs (92% of hGH primary suspect reports vs 84% of insulin primary suspect reports). Lot number completion rates were generally low, with a higher incidence for insulin drugs than for hGH drugs (37% of insulin primary suspect reports vs 13% of hGH primary suspect reports). There were 13.5% of insulin reports that could not be linked to manufacturers, while 7.5% of hGH reports could not be linked to a manufacturer.The completion and accuracy rates of FAERS data on biologics observed in this study are consistent with those observed in earlier studies and suggest that traceability in adverse event reports can be improved through more consistent use of brand names or other product specific identifiers and through more frequent inclusion of lot numbers.

Existing mammographic screening solutions are generally associated with several major drawbacks, such as exposure to ionizing radiation or insufficient sensitivity in younger populations with radiographically-dense breast. Even when combined with ultrasound or magnetic resonance imaging, X-Ray mammography may still attain unspecific or false positive results. Thus, development of new breast imaging tools represents a timely medical challenge. We report on a new approach to high-resolution functional and anatomical breast angiography using volumetric hand-held optoacoustic tomography, which employs light intensities safe for human use. Experiments in young healthy volunteers with fibroglandular-dominated dense breasts revealed the feasibility of rendering three-dimensional images representing vascular anatomy and functional blood oxygenation parameters at video rate. Sufficient contrast was achieved at depths beyond 2 cm within dense breasts without compromising the real-time imaging performance. The suggested solution may thus find applicability as a standalone or supplemental screening tool for early detection and follow-up of carcinomas in radiographically-dense breasts. Volumetric handheld optoacoustic tomography scanner uses safe pulses of near-infrared light to render three-dimensional images of deep vascular anatomy, blood oxygenation and breast parenchyma at video rate.

This chapter reviews important aspects of pharmacovigilance of biosimilars. Biologics are structurally complex molecules that are more difficult to characterize, produce, and reproduce than most small-molecule compounds. Ongoing robust pharmacovigilance is critical in the monitoring, detection, and assessment of safety signals over the life cycle of every biologic. The availability of multisource biologics, including biosimilars, warrants rigorous pharmacovigilance to accurately detect and disaggregate safety signals. Although biosimilars are highly similar to their reference biologics, they are not required or expected to be identical, and regulatory pathways permit slight variations in structural and pharmaceutical attributes and clinical development approaches. During development, candidate biosimilars are evaluated in a stepwise manner against their reference product for similarity in structure, function, clinical efficacy, and safety. However, clinical studies to evaluate biosimilarity may not detect rare adverse events, and potential differences in safety resulting from minor differences in manufacturing procedures between a biosimilar and its reference product (or other biosimilars) may not be detected before approval. Risk management plans, particularly during the early postmarketing period, are also an important component of pharmacovigilance planning for biosimilars. Important components of pharmacovigilance programs include ongoing and rigorous data collection, adverse event reporting, and analysis of causal relationships resulting in accurate attribution of an adverse event to the correct product. Methods to improve product-specific monitoring, like the assignment of distinguishable nonproprietary names for all biologics and the use of additional product identifiers (e.g., batch number, trade name, manufacturer) for adverse event reporting, are vital to ensure accurate surveillance and traceability of all biologics, including biosimilars.

This retrospective analysis assessed the capability of active and passive safety surveillance systems to track product-specific safety events in the USA for branded and generic enoxaparin, a complex injectable subject to immune-related and other adverse events (AEs).Analysis of heparin-induced thrombocytopenia (HIT) incidence was performed on benefit claims for commercial and Medicare supplemental-insured individuals newly treated with enoxaparin under pharmacy benefit (1 January 2009 - 30 June 2012). Additionally, spontaneous reports from the FDA AE Reporting System were reviewed to identify incidence and attribution of enoxaparin-related reports to specific manufacturers.Specific, dispensed products were identifiable from National Drug Codes only in pharmacy-benefit databases, permitting sensitive comparison of HIT incidence in nearly a third of patients treated with brand or generic enoxaparin. After originator medicine's loss of exclusivity, only 5% of spontaneous reports were processed by generic manufacturers; reports attributable to specific generics were approximately ninefold lower than expected based on market share.Claims data were useful for active surveillance of enoxaparin generics dispensed under pharmacy benefits but not for products administered under medical benefits. These findings suggest that the current spontaneous reporting system will not distinguish product-specific safety signals for products distributed by multiple manufacturers, including biosimilars.

Imaging dynamics in living organisms is essential for the understanding of biological complexity. While multiple imaging modalities are often required to cover both microscopic and macroscopic spatial scales, dynamic phenomena may also extend over different temporal scales, necessitating the use of different imaging technologies based on the trade-off between temporal resolution and effective field of view. Optoacoustic (photoacoustic) imaging has been shown to offer the exclusive capability to link multiple spatial scales ranging from organelles to entire organs of small animals. Yet, efficient visualization of multi-scale dynamics remained difficult with state-of-the-art systems due to inefficient trade-offs between image acquisition and effective field of view. Herein, we introduce a spiral volumetric optoacoustic tomography (SVOT) technique that provides spectrally-enriched high-resolution optical absorption contrast across multiple spatio-temporal scales. We demonstrate that SVOT can be used to monitor various in vivo dynamics, from video-rate volumetric visualization of cardiac-associated motion in whole organs to high-resolution imaging of pharmacokinetics in larger regions. The multi-scale dynamic imaging capability thus emerges as a powerful and unique feature of the optoacoustic technology that adds to the multiple advantages of this technology for structural, functional and molecular imaging.

Approval of the first biosimilar in the USA may occur by the end of 2014, yet a naming approach for biosimilars has not been determined. Biosimilars are highly similar to their biologic reference product but are not identical to it, because of their structural complexity and variations in manufacturing processes among companies. There is a need for a naming approach that can distinguish a biosimilar from its reference product and other biosimilars and ensure accurate tracing of adverse events (AEs) to the administered product. In contrast, generic small-molecule drugs are identical to their reference product and, therefore, share the same nonproprietary name. Clinical trials required to demonstrate biosimilarity for approval may not detect rare AEs or those occurring after prolonged use, and the incidence of such events may differ between a biosimilar and its reference product. The need for precise biologic identification is further underscored by the possibility of biosimilar interchangeability, a US designation that will allow substitution without prescriber intervention. For several biologics, the US Food and Drug Administration (FDA) has used a naming approach that adds a prefix to a common root nonproprietary name, enabling healthcare providers to distinguish between products, avoid medication errors, and facilitate pharmacovigilance. We recommend that the FDA implement a biosimilars naming policy that likewise would add a distinguishable prefix or suffix to the root nonproprietary name of the reference product. This approach would ensure that a biosimilar could be distinguished from its reference product and other biosimilars in patient records and pharmacovigilance databases/reports, facilitating accurate attribution of AEs.

Chronic venous insufficiency (CVI) is one of the most common medical conditions with reported prevalence estimates as high as 30% in the adult population. Although conservative management with compression therapy may improve the symptoms associated with CVI, healing often demands invasive procedures. Besides established surgical methods like vein stripping or bypassing, endovenous laser therapy (ELT) emerged as a promising novel treatment option during the last 15 years offering multiple advantages such as less pain and faster recovery. Much of the treatment success hereby depends on monitoring of the treatment progression using clinical imaging modalities such as Doppler ultrasound. The latter however do not provide sufficient contrast, spatial resolution and three-dimensional imaging capacity which is necessary for accurate online lesion assessment during treatment. As a consequence, incidence of recanalization, lack of vessel occlusion and collateral damage remains highly variable among patients. In this study, we examined the capacity of volumetric optoacoustic tomography (VOT) for real-time monitoring of ELT using an ex-vivo ox foot model. ELT was performed on subcutaneous veins while optoacoustic signals were acquired and reconstructed in real-time and at a spatial resolution in the order of 200μm. VOT images showed spatio-temporal maps of the lesion progression, characteristics of the vessel wall, and position of the ablation fiber’s tip during the pull back. It was also possible to correlate the images with the temperature elevation measured in the area adjacent to the ablation spot. We conclude that VOT is a promising tool for providing online feedback during endovenous laser therapy.

Accurate visualization of biological events occurring on a sub-second scale requires high frame rate acquisition of image data from living tissues. Yet, fast imaging performance commonly comes at the cost of limited field-of-view and reduced image quality. Here, we report on a small-animal optoacoustic tomographic imaging concept based on scanning of a spherical detection array. The suggested approach delivers whole-body images of unparalleled quality while retaining real-time volumetric imaging capability within selected regions at the whole organ scale. Imaging performance was tested in tissue-mimicking phantoms and living animals, attaining nearly isotropic three-dimensional spatial resolution in the range of 250–500 μm across fields of view covering the entire mouse body. The system maintained high volumetric imaging rates of 100 frames per second within volumes of up to 1.5 cm3, which further allowed visualizing the fast motion of a beating mouse heart without gating the acquisition. The newly introduced approach is ideally suited for acquisition of both real-time and whole-body volumetric image data, thus offering powerful capacities for simultaneous anatomical, functional, and molecular imaging with optoacoustics.

Endovenous laser therapy (ELT) was introduced in clinical practice for treating incompetent veins about fifteen years ago. Despite the considerable clinical evidence collected so far, no rigorous guidelines are yet available regarding the optimal energy deposition protocols while incidence of recanalization, lack of vessel occlusion and collateral damage remains variable among patients. Online monitoring and feedback-based control over the lesion progression may improve clinical outcomes. Yet the currently employed monitoring tools, such as Doppler ultrasound, often do not provide sufficient contrast as well as three-dimensional imaging capacity for accurate lesion assessment during thermal treatments. Here we investigate on the utility of volumetric optoacoustic tomography for real-time monitoring of the ELT procedures. Experiments performed in subcutaneous veins of an ox foot model revealed the accurate spatio-temporal maps of the lesion progression and characteristics of the vessel wall. Optoacoustic images further correlated with the temperature elevation measured in the area adjacent to the coagulation spot and made it possible to track the position of the fiber tip during its pull back in real time and in all three dimensions. Overall, we showcase that volumetric optoacoustic tomography is a promising tool for providing online feedback during endovenous laser therapy.

Multispectral optoacoustic tomography offers unprecedented capabilities in biological research and newly-developed systems prompt the clinical translation of this modality. By exciting tissues at multiple optical wavelengths, the distribution of spectrally-distinctive absorbers can be resolved with high resolution in deep tissues, thus enabling reading important biological parameters such as blood oxygenation or the biodistribution of photo-absorbing agents. Multispectral three-dimensional optoacoustic imaging generally comes at the expense of slow acquisition times, which limits the dynamic imaging capabilities of this modality. Recently, the feasibility of multispectral three-dimensional imaging in real time (five dimensional imaging) has been showcased. Two different illumination strategies can be used for this purpose. The first approach is based on tuning the wavelength of the laser on a per-pulse basis, which enables acquisition of large multispectral datasets on a very short time. The second approach is based on properly synchronizing the light beams from two (or more) laser sources. The performances of these two approaches are compared and discussed herein based on experiments with mice and human volunteers.

We present a technique for fully noninvasive acquisition of real-time volumetric multispectral optoacoustic data from whole mouse brain. The neuroimaging capacity of the new methodology is demonstrated here by simultaneous label-free assessment of multiple stimulus-evoked hemodynamic responses, including blood oxygenation, total hemoglobin, cerebral blood volume, oxygenized and deoxygenized hemoglobin.

We report on an optoacoustic imaging system capable of acquiring volumetric multispectral optoacoustic data in real time. The system is based on simultaneous acquisition of optoacoustic signals from 256 different tomographic projections by means of a spherical matrix array. Thereby, volumetric reconstructions can be done at high frame rate, only limited by the pulse repetition rate of the laser. The developed tomographic approach presents important advantages over previously reported systems that use scanning for attaining volumetric optoacoustic data. First, dynamic processes, such as the biodistribution of optical biomarkers, can be monitored in the entire volume of interest. Second, out-of-plane and motion artifacts that could degrade the image quality when imaging living specimens can be avoided. Finally, real-time 3D performance can obviously save time required for experimental and clinical observations. The feasibility of optoacoustic imaging in five dimensions, i.e. real time acquisition of volumetric datasets at multiple wavelengths, is reported. In this way, volumetric images of spectrally resolved chromophores are rendered in real time, thus offering an unparallel imaging performance among the current bio-imaging modalities. This performance is subsequently showcased by video-rate visualization of in vivo hemodynamic changes in mouse brain and handheld visualization of blood oxygenation in deep human vessels. The newly discovered capacities open new prospects for translating the optoacoustic technology into highly performing imaging modality for biomedical research and clinical practice with multiple applications envisioned, from cardiovascular and cancer diagnostics to neuroimaging and ophthalmology.

Pulse-echo ultrasound and optoacoustic imaging possess very different, yet highly complementary, advantages of mechanical and optical contrast in living tissues. Integration of pulse-echo ultrasound with optoacoustic imaging may therefore significantly enhance the potential range of clinical applications. Nonetheless, efficient integration of these modalities remains challenging owing to the fundamental differences in the underlying physical contrast, optimal signal acquisition and image reconstruction approaches. We report on a new method for hybrid three-dimensional optoacoustic and pulse-echo ultrasound imaging based on passive generation of ultrasound with a spherical optical absorber, thus avoiding the hardware complexity of active ultrasound generation. The proposed approach allows for acquisition of complete hybrid datasets with a single laser interrogation pulse, resulting in simultaneous rendering of ultrasound and optoacoustic images at a rate of 10 volumetric frames per second. Real time image rendering for both modalities is enabled by using parallel GPU-based implementation of the reconstruction algorithms. Performance is first characterized in tubing phantoms followed by in vivo measurements in healthy human volunteers, confirming general clinical applicability of the method. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

Current functional neuroimaging methods are not adequate for high-resolution whole-brain visualization of neural activity in real time. Here, we show imaging of fast hemodynamic changes in deep mouse brain using fully noninvasive acquisition of five-dimensional optoacoustic data from animals subjected to oxygenation stress. Multispectral video-rate acquisition of three-dimensional tomographic data enables simultaneous label-free assessment of multiple brain hemodynamic parameters, including blood oxygenation, total hemoglobin, cerebral blood volume, oxygenized and deoxygenized hemoglobin, in real time. The unprecedented results indicate that the proposed methodology may serve as a powerful complementary, and potentially superior, method for functional neuroimaging studies in rodents.

Ultrasonography and optoacoustic imaging share powerful advantages related to the natural aptitude for real-time image rendering with high resolution, the hand-held operation, and lack of ionizing radiation. The two methods also possess very different yet highly complementary advantages of the mechanical and optical contrast in living tissues. Nonetheless, efficient integration of these modalities remains challenging owing to the fundamental differences in the underlying physical contrast, optimal signal acquisition, and image reconstruction approaches. We report on a method for hybrid acquisition and reconstruction of three-dimensional pulse-echo ultrasound and optoacoustic images in real time based on passive ultrasound generation with an optical absorber, thus avoiding the hardware complexity of active ultrasound generation. In this way, complete hybrid datasets are generated with a single laser interrogation pulse, resulting in simultaneous rendering of ultrasound and optoacoustic images at an unprecedented rate of 10 volumetric frames per second. Performance is subsequently showcased in phantom experiments and in-vivo measurements from a healthy human volunteer, confirming general clinical applicability of the method.

Abstract Growing global demand for hydrocarbons has forced key operators to expand field developments towards deeper waters and remoter areas with increasing step out distances. At the same time, brownfields already in production are facing high water cut and low reservoir pressure; these scenarios have created a demand for more powerful subsea pump systems. FMC Technologies and Sulzer Pumps have jointly collaborated to develop a new multiphase pump system. This new solution is a helico-axial pump that is driven by an innovative 3.2 MW permanent magnet motor (PMM). This subsea pump is distinguished by its high power and efficiency, with a design optimized for the seabed environment. PMM technology has been applied and proven for topside and onshore applications but now is also qualified for subsea use. The key advantage of using PMM is the high power density, the ability to operate at higher speeds and improved efficiency in a more compact design compared to traditional induction motors, these key differentiators are of significant benefit to subsea processing production schemes. The pump unit proven during the qualification program was designed for water depths of up to 2000 m [6562 ft], internal pressure rating of 345bar [5000 psi], and a design temperature of 80°C [176°F] and furnished with helico-axial multiphase hydraulics and a highly tolerant water-based barrier fluid (coolant/lubricant/motor pressurization fluid). Radial hydraulics are also available, as well as a combination of helico-axial and radial (hybrid hydraulic) depending on gas volume fraction (GVF). A full size subsea pump system, complete with motor, pump cartridge, fluid conditioning system, process control and additional systems was engineered and constructed and installed at a purpose-built pump test facility able to simulate multiphase field operational conditions. The initial qualification test program of the 3.2 MW, 5000 psi multiphase pump module is now complete and complementary system endurance testing is reaching conclusion. This paper presents an overview of the key features of the pump and motor system, and the qualification program to which this boosting system was subjected. The paper also will describe case studies and the pump selection criteria for these scenarios. Introduction Electric submersible pumps (ESP) have been broadly applied in, or adjacent to, subsea wells in order to provide additional energy to the reservoirs. The early adoption of ESPs was a natural choice as they were already suitable for submerged environments, however as this type of pump was designed for downhole installation its geometry featured small diameters and long lengths. Short mean time between maintenance (MTBM), high costs of intervention and lost production during maintenance led oil companies to look for alternative pump solutions. Despite multiple design iterations in both vertical and horizontal configurations for mudline pump motor units using ESPs, the systems continued to suffer from short MTBM and other limitations due to the geometrical constraints resulting in a very low power density pump system. Since the pump installation location has evolved away from being downhole, the diameter limitations no longer apply and thus a shorter motor-pump unit with higher power density can be realized, facilitating installation and intervention activities. Furthermore, the consequent reduction of the number of pump stages improves rotordynamic behavior and allows the development of more powerful and reliable machines.

Biosimilars are biologic medicines that are highly similar to approved biologics, notwithstanding minor differences in clinically inactive components. Since 2007, biosimilars have been approved for use in patients in the European Union (EU) and other regions. European experience provides several lessons as the United States (US) healthcare system prepares for biosimilar approvals. These lessons emphasize the need for adequate efficacy and safety studies, post-marketing surveys and a robust pharmacovigilance system that can accurately track and trace biologics, including biosimilars and their reference products, from the patient to the manufacturer.We review the EU experience with biosimilar pharmacovigilance and discuss the implications for biosimilar pharmacovigilance in the USA. Furthermore, we review several aspects of biosimilar pharmacovigilance, including cohort event monitoring, traceability, biosimilar interchangeability, pharmacovigilance system development, nomenclature and counterfeit tracking.The availability of biosimilars as lower-cost biologics must carefully consider issues of safety, efficacy and traceability. Stringent pharmacovigilance procedures are required to detect potential differences in safety signals between biosimilars and their reference products. Pharmacovigilance of biologics should include processes that are easily used by prescribing practitioners to ensure that data are consistent and new safety signals are properly reported and assigned to the correct product.

Imaging dynamics at different temporal and spatial scales is essential for understanding the biological complexity of living organisms, disease state and progression. Optoacoustic imaging has been shown to offer exclusive applicability across multiple scales with excellent optical contrast and high resolution in deep-tissue observations. Yet, efficient visualization of multi-scale dynamics remained difficult with state-of-the-art systems due to inefficient trade-offs between image acquisition time and effective field of view. Herein, we introduce the spiral volumetric optoacoustic tomography technique that provides spectrally enriched high-resolution contrast across multiple spatiotemporal scales. In vivo experiments in mice demonstrate a wide range of dynamic imaging capabilities, from three-dimensional high-frame-rate visualization of moving organs and contrast agent kinetics in selected areas to whole-body longitudinal studies with unprecedented image quality. The newly introduced paradigm shift in imaging of multi-scale dynamics adds to the multifarious advantages provided by the optoacoustic technology for structural, functional and molecular imaging. A rapid-fire laser technique from researchers in Germany can image the entire body of a living mouse in sharp, three-dimensional detail. Optoacoustic imaging uses nanosecond-long laser pulses to briefly heat tissue, creating ultrasonic pressure waves that can be used to non-invasively detect tissue shapes. Switching between fields of view in this technique often requires unsafe acquisition times, but Luis Dean-Ben from the Helmholtz Zentrum Munchen research institute and colleagues have solved this issue with spiral volumetric optoacoustic tomography. In this method, the laser beam follows a spiral trajectory around a live mouse and pressure waves are spotted using a spherical detector with 256 sensitive elements. On-the-fly image rendering could capture dynamic events at millisecond time scales, such as beat-by-beat characterization of heart motion to whole-body studies of the growth of breast cancer tumours.

OBJECTIVES: In patients with suspected acute coronary syndrome (ACS), rapid triage is essential. The aim of this study was to establish a tool for risk prediction of 30-day cardiac events (CE) on admission. 30-day cardiac events (CE) were defined as early coronary revascularization, subsequent myocardial infarction, or cardiovascular death within 30 days. METHODS AND RESULTS: This single-centre, prospective cohort study included 377 consecutive patients presenting to the emergency department with suspected ACS and for whom troponin T measurements were requested on clinical grounds. Fifteen biomarkers were analyzed in the admission sample, and clinical parameters were assessed by the TIMI risk score for unstable angina/Non-ST myocardial infarction and the GRACE risk score. Sixty-nine (18%) patients presented with and 308 (82%) without ST-elevations, respectively. Coronary angiography was performed in 165 (44%) patients with subsequent percutaneous coronary intervention - accounting for the majority of CE - in 123 (33%) patients, respectively. Eleven out of 15 biomarkers were elevated in patients with CE compared to those without. High-sensitive troponin T (hs-cTnT) was the best univariate biomarker to predict CE in Non-ST-elevation patients (AUC 0.80), but did not yield incremental information above clinical TIMI risk score (AUC 0.80 vs 0.82, p = 0.69). Equivalence testing of AUCs of risk models and non-inferiority testing demonstrated that the clinical TIMI risk score alone was non-inferior to its combination with hs-cTnT in predicting CE. CONCLUSIONS: In patients presenting without ST-elevations, identification of those prone to CE is best based on clinical assessment based on TIMI risk score criteria and hs-cTnT.

Introduction The under-reporting of adverse drug events (ADEs) is an international health concern. A number of studies have assessed the root causes but, to our knowledge, little information exists relating under-reporting to practices and systems used for the recording and tracking of drug‐related adverse event observations in ambulatory settings, institutional settings, and retail pharmacies. Objectives Our objective was to explore the process for reporting ADEs in US hospitals, ambulatory settings, and retail pharmacies; to explore gaps and inconsistencies in the reporting process; and to identify the causes of under-reporting ADEs in these settings. Methods The Tufts Center for the Study of Drug Development (Tufts CSDD) interviewed 11 thought leaders and conducted a survey between May and August 2014 among US-based healthcare providers (HCPs) in diverse settings to assess their experiences with, and processes for, reporting ADEs. Results A total of 123 individuals completed the survey (42 % were pharmacists; 27 % were nurses; 15 % were physicians; and 16 % were classified as ‘other’). HCPs indicated that the main reasons for under-reporting were difficulty in determining the cause of the ADE, given that most patients receive multiple therapies simultaneously (66 % of respondents); that HCPs lack sufficient time to report ADEs (63 % of respondents); poor integration of ADE-reporting systems (53 % of respondents); and uncertainty about reporting procedures (52 % of respondents). Discussion The results of this pilot study identify that key factors contributing to the under-reporting of ADEs relate to a lack of standardized process, a lack of training and education, and a lack of integrated health information technologies. Electronic supplementary material The online version of this article (doi:10.1007/s40264-016-0455-4) contains supplementary material, which is available to authorized users.

Aims Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite IGC. Methods and results p66Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66Shc, performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66Shc expression and ROS generation. Conclusions In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.

The aim of this study was to evaluate the influence of unilateral reduction of afferent input on the 'neural coupling' mechanism during cooperative hand movements. This 'neural coupling' is reflected in the task-specific appearance of contralateral reflex responses in forearm muscles to unilateral arm nerve stimulation. Sensory input from the right hand was reduced by ischemic nerve block at the right wrist. Ipsilateral and contralateral reflex responses elicited by stimulation of the ulnar nerve either at the left or the right wrist proximal to the nerve block were recorded in forearm extensors during the performance of cooperative hand movements. During ischemia of the right hand, a significant difference was found in the magnitude of the contralateral responses, that is, contralateral reflex responses in the right arm were significantly higher compared with the left arm (P=0.04). Ipsilateral reflex responses were not affected by ischemic nerve block. The reduced afference from the ischemic hand during cooperative hand movements is assumed to weaken the activity in ipsilateral pathways involved in the neural coupling mechanism. Consequently, a shift in the interhemispheric balance might lead to the relative increase and decrease in the contralateral responses to left and right nerve stimulation, respectively. The study provides novel information on the involvement of ipsilateral hemispheres in the performance of cooperative hand movements.