Simulation of pH level distribution inside a coiled flow inverter for continuous low pH viral inactivation.

The continuous production of monoclonal antibodies (mAbs) with the help of disposable equipment poses one of the future major changes in the pharmaceutical industry. Consequently, continuous viral clearance needs to be developed as well. The coiled flow inverter (CFI) was successfully implemented in the continuous downstream as a residence time module for low pH viral inactivation. As the elution profile of the upstream continuously operated protein A chromatography results in fluctuating pH values, the pH level distribution inside the CFI is highly relevant. This study presents a detailed investigation of pH level distribution inside the CFI at varying inlet conditions with the help of computational fluid dynamics simulation. The simulation model was validated first with the help of experimental data. Afterwards, the model was used for further investigations. It was determined that with a pH sine curve as input, the duration until steady state at the outlet requires two times the minimum residence time of the apparatus. Moreover, it could be observed that the CFI itself offers a progressive dampening effect on the pH level distribution. Afterwards, different forms of the sine curve representing different operation modes of the continuous protein A chromatograph were tested to evaluate this dampening capability. It became clear that the switch time has the highest influence on the resulting pH of the outlet stream and should be considered for process development. Finally, the radial pH profiles at different positions inside the CFI were determined. This once again revealed the high radial mixing capability of the CFI and its influence on the resulting product stream.

Simulation of continuous low pH viral inactivation inside a coiled flow inverter.

Continuous production of monoclonal antibodies is gaining more and more importance. To ensure continuous flow through the entire process as well as viral safety, continuous viral clearance needs to be investigated as well. This study focuses on low pH viral inactivation inside a coiled flow inverter (CFI). Computational fluid dynamics (CFD) simulation is used to gain further insight into the inactivation process inside the apparatus. The influence of viruses in comparison to different tracer elements on the residence time distribution (RTD) behavior is investigated. Finally, the viral inactivation kinetics are implemented into the CFD simulation and real process conditions are simulated. These are compared to experimental results. To the authors' knowledge, this study represents the first successful simulation of continuous viral inactivation inside a CFI. It allows the detailed analysis of processes inside the apparatus and the prediction of experimental virus study results and will therefore contribute to the effective planning of future validation studies.

Side-by-side comparability of batch and continuous downstream for the production of monoclonal antibodies.

Continuous processing is the future production method for monoclonal antibodies (mAbs). A fully continuous, fully automated downstream process based on disposable equipment was developed and implemented inside the MoBiDiK pilot plant. However, a study evaluating the comparability between batch and continuous processing based on product quality attributes was not conducted before. The work presented fills this gap comparing both process modes experimentally by purifying the same harvest material (side-by-side comparability). Samples were drawn at different time points and positions in the process for batch and continuous mode. Product quality attributes, product-related impurities, as well as process-related impurities were determined. The resulting polished material was processed to drug substance and further evaluated regarding storage stability and degradation behavior. The in-process control data from the continuous process showed the high degree of accuracy in providing relevant process parameters such as pH, conductivity, and protein concentration during the entire process duration. Minor differences between batch and continuous samples are expected as different processing conditions are unavoidable due to the different nature of batch and continuous processing. All tests revealed no significant differences in the intermediates and comparability in the drug substance between the samples of both process modes. The stability study of the final product also showed no differences in the stability profile during storage and forced degradation. Finally, online data analysis is presented as a powerful tool for online-monitoring of chromatography columns during continuous processing.

Virus study for continuous low pH viral inactivation inside a coiled flow inverter.

Continuous processing for the production of monoclonal antibodies (mAb) gains more and more importance. Several solutions exist for all the necessary production steps, leading to the possibility to build fully continuous processes. Low pH viral inactivation is a part of the standard platform process for mAb production. Consequently, Klutz et al. introduced the coiled flow inverter (CFI) as a tool for continuous low pH viral inactivation. Besides theoretical calculations of viral reduction, no viral clearance study has been presented so far. In addition, the validation of continuous viral clearance is often neglected in the already existing studies for continuous processing. This study shows in detail the development and execution of a virus study for continuous low pH viral inactivation inside a CFI. The concept presented is also valid for adaptation to other continuous viral clearance steps. The development of this concept includes the technical rationale for an experimental setup, a valid spiking procedure, and finally a sampling method. The experimental results shown represent a viral study using xenotropic murine leukemia virus as a model virus. Two different protein A (ProtA) chromatography setups with varying pH levels were tested. In addition, one of these setups was tested against a batch experiment utilizing the same process material. The results show that sufficient low pH viral inactivation (decadic logarithm reduction value >4) was achieved in all experiments. Complete viral inactivation took place within the first 14.5 min for both continuous studies and the batch study, hence showing similar results. This study therefore represents a successful virus study concept and experiment for a continuous viral inactivation step. Moreover, it was shown that the transfer from batch results to the continuous process is possible. This is accomplished by the narrow residence time distribution of the CFI, showing how close the setup approaches the ideal plug flow and with that batch operation.

Delineating optimal settlement areas of juvenile reef fish in Ngederrak Reef, Koror state, Republic of Palau.

Establishing the effectiveness of habitat features to act as surrogate measures of diversity and abundance of juvenile reef fish provides information that is critical to coral reef management. When accurately set on a broader spatial context, microhabitat information becomes more meaningful and its management application becomes more explicit. The goal of the study is to identify coral reef areas potentially important to juvenile fishes in Ngederrak Reef, Republic of Palau, across different spatial scales. To achieve this, the study requires the accomplishment of the following tasks: (1) structurally differentiate the general microhabitat types using acoustics; (2) quantify microhabitat association with juvenile reef fish community structure; and (3) conduct spatial analysis of the reef-wide data and locate areas optimal for juvenile reef fish settlement. The results strongly suggest the importance of branching structures in determining species count and abundance of juvenile reef fish at the outer reef slope of Ngederrak Reef. In the acoustic map, the accurate delineation of these features allowed us to identify reef areas with the highest potential to harbor a rich aggregation of juvenile reef fish. Using a developed spatial analysis tool that ranks pixel groups based on user-defined parameters, the reef area near the Western channel of Ngederrak is predicted to have the most robust aggregation of juvenile reef fish. The results have important implications not only in management, but also in modeling the impacts of habitat loss on reef fish community. At least for Ngederrak Reef, the results advanced the utility of acoustic systems in predicting spatial distribution of juvenile fish.

Feeding Value of Lupins, Field Peas, Faba Beans and Chickpeas for Poultry: An Overview.

Grain legumes are fair sources of protein, amino acids and energy, and can be used as a replacement for soybean meal in poultry feed formulations as the soybean meal becomes short in supply and costly. However, a concern associated with the use of grain legumes in poultry feeding is the presence of antinutritional factors. The effective processing and utilisation of these grain legumes in poultry feeding are well documented. The current review focuses on four selected grain legumes (lupins [Lupinus albus and Lupinus angustifolius], field peas [Phaseolus vulgaris], faba beans [Vicia faba] and chickpeas [Cicer arietinum]) and their nutrient content, the presence of antinutritional factors, processing methods and feeding value, including updated data based on recent research findings.

Early ICD implantation following out-of-hospital cardiac arrest: a retrospective cohort study from the Swedish Registry for Cardiopulmonary Resuscitation.

BACKGROUND: It is unclear whether an implantable cardioverter-defibrillator (ICD) is generally beneficial in survivors of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: We studied the association between ICD implantation prior to discharge and survival in patients with cardiac aetiology or initial shockable rhythm in OHCA. DESIGN: We conducted a retrospective cohort study in the Swedish Registry for Cardiopulmonary Resuscitation. Treatment associations were estimated using propensity scores. We used gradient boosting, Bayesian additive regression trees, neural networks, extreme gradient boosting and logistic regression to generate multiple propensity scores. We selected the model yielding maximum covariate balance to obtain weights, which were used in a Cox regression to calculate HRs for death or recurrent cardiac arrest. PARTICIPANTS: All cases discharged alive during 2010 to 2020 with a cardiac aetiology or initial shockable rhythm were included. A total of 959 individuals were discharged with an ICD, and 2046 were discharged without one. RESULTS: Among those experiencing events, 25% did so within 90 days in the ICD group, compared with 52% in the other group. All HRs favoured ICD implantation. The overall HR (95% CI) for ICD versus no ICD was 0.38 (0.26 to 0.56). The HR was 0.42 (0.28 to 0.63) in cases with initial shockable rhythm; 0.18 (0.06 to 0.58) in non-shockable rhythm; 0.32 (0.20 to 0.53) in cases with a history of coronary artery disease; 0.36 (0.22 to 0.61) in heart failure and 0.30 (0.13 to 0.69) in those with diabetes. Similar associations were noted in all subgroups. CONCLUSION: Among survivors of OHCA, those discharged with an ICD had approximately 60% lower risk of death or recurrent cardiac arrest. A randomised trial is warranted to study this further.

Well-being and internal resources during the COVID-19 pandemic in relation to meaning in life and existential anxiety.

The COVID-19 pandemic represents an event that placed humanity in a context where confrontation with uncertainty, isolation, life threats, and significant changes in one's life were on a scale that exceeded by far any previous individual or community crises. The interest of the present research was to investigate the relationship between meaning in life (MiL) and existential anxiety (EA) with personal internal resources such as creativity, playfulness, well-being, and personal meaning. A total of 451 participants from 48 countries (mean age 34.93 years, standard deviation 12.62, 31.9% men, 67.4% women) were questioned via online questionnaires between May and June 2020. Cluster analysis was performed on the meaning in life and existential anxiety that generated four categories of persons: Reactive, Superficial, Preoccupied, and Dedicated. Well-being and internal resources were associated mostly with the Dedicated type and less with the Reactive one. Arguments relying on the existential positive psychology suffering model and the hostile world scenario are presented to support the results and plead for interventions that elicit meaning, stimulate creativity, and guide people in finding purpose in order to ultimately promote psychological and mental health.

Calcium Nutrition of Broilers: Current Perspectives and Challenges.

Calcium (Ca) plays an essential role in poultry nutrition as 99% of Ca is located in birds' skeletal system. However, oversupply of Ca rather than deficiency of Ca is the current concern in commercial broiler diets. Calcium is an inexpensive dietary nutrient due to the cheap and abundant availability of limestone, the major Ca source; therefore, little attention was given to the oversupply of Ca in the past. The recent shift in the use of digestible P in broiler feed formulations has necessitated a closer look at digestible Ca, as Ca and P are interrelated in their absorption and postabsorptive utilisation. In this context, data on ileal digestibility of Ca and P in ingredients has been determined. Preliminary data on the digestible Ca and digestible P requirements for the different growth stages of broilers have also recently become available. The present review focusses on these recent advances in Ca nutrition. In addition, aspects of homeostatic control mechanisms, different Ca sources and factors influencing Ca digestibility in poultry are covered.

Elastic Deformation of Optical Coherence Tomography Images of Diabetic Macular Edema for Deep-Learning Models Training: How Far to Go?

- Objective: To explore the clinical validity of elastic deformation of optical coherence tomography (OCT) images for data augmentation in the development of deep-learning model for detection of diabetic macular edema (DME). METHODS: Prospective evaluation of OCT images of DME (n = 320) subject to elastic transformation, with the deformation intensity represented by ([Formula: see text]). Three sets of images, each comprising 100 pairs of scans (100 original & 100 modified), were grouped according to the range of ([Formula: see text]), including low-, medium- and high-degree of augmentation; ([Formula: see text] = 1-6), ([Formula: see text] = 7-12), and ([Formula: see text] = 13-18), respectively. Three retina specialists evaluated all datasets in a blinded manner and designated each image as 'original' versus 'modified'. The rate of assignment of 'original' value to modified images (false-negative) was determined for each grader in each dataset. RESULTS: The false-negative rates ranged between 71-77% for the low-, 63-76% for the medium-, and 50-75% for the high-augmentation categories. The corresponding rates of correct identification of original images ranged between 75-85% ([Formula: see text]0.05) in the low-, 73-85% ([Formula: see text]0.05 for graders 1 & 2, p = 0.01 for grader 3) in the medium-, and 81-91% ([Formula: see text]) in the high-augmentation categories. In the subcategory ([Formula: see text] = 7-9) the false-negative rates were 93-83%, whereas the rates of correctly identifying original images ranged between 89-99% ([Formula: see text]0.05 for all graders). CONCLUSIONS: Deformation of low-medium intensity ([Formula: see text] = 1-9) may be applied without compromising OCT image representativeness in DME. Clinical and Translational Impact Statement-Elastic deformation may efficiently augment the size, robustness, and diversity of training datasets without altering their clinical value, enhancing the development of high-accuracy algorithms for automated interpretation of OCT images.

Minimally Invasive Technique for Choroidal Fluid Drainage.

BACKGROUND: This study describes a simple technique for the treatment of kissing choroidal detachment. In contrast to the commonly used technique, this technique is minimally invasive, fast, sutureless, and does not require access to the vitreous space. METHODS: A maintainer is inserted into the anterior chamber. A 25G trocar is inserted at the pars plana into the suprachoroidal space. Drainage is evident by the clear yellowish fluid freely emerging through the trocar, accompanied with deepening of the anterior chamber and an increase in the red reflex. RESULTS: Follow-up ultrasound 1 week after the surgery demonstrated resolution of the choroidal detachment. Net surgery time is about 10 minutes. No complications were noted. DISCUSSION: This is the first report of the technique performed in phakic eye, with video description of the steps and real-time clues for successful drainage even with reduced posterior segment visibility due to lens opacities.

Evolution of Glaucoma Surgery in the Last 25 Years.

Glaucoma is a chronic neurodegenerative optic nerve disease. Treatment is intended to prevent the development and progression of optic nerve damage by lowering intraocular pressure (IOP). Current therapy options include topical/systemic drugs that increase aqueous humor outflow or decrease its production, laser therapy that targets the trabecular meshwork and ciliary body, and incisional surgery. Trabeculectomy as well as glaucoma drainage devices are often performed, given their high efficacy in lowering IOP. However, the significant risk profile with potential sight-threatening complications has motivated glaucoma experts to create alternative surgeries to treat glaucoma. Minimally invasive glaucoma surgery (MIGS) is defined by: micro-invasive approach, minimal tissue trauma, high safety profile, and rapid recovery. The new devices might promote an earlier transition from medical/laser therapy to surgery, and therefore decrease the side effects associated with long-term use of topical medications as well as deal with the limited adherence of patients to their regimens. This review presents the surgical options available for glaucoma patients and their evolution over the past 25 years.

Insights into the dynamics of harmful algal blooms in a tropical estuary through an integrated hydrodynamic-Pyrodinium-shellfish model.

In contrast to temperate Harmful Algal Blooms (HABs), knowledge on the mechanisms driving tropical HABs are less well studied. The interaction of a seasonal temperature window, cysts (for certain species) and large-scale transport are some of the key processes in temperate HABs. In the Philippines, HABs occur not along long open coastlines, but in embayments that are highly influenced by run-off and stratification. These embayments are typically also the sites of cultured or wild harvest shellfish and other aquaculture activities. Sorsogon Bay in the northeastern Philippines has experienced prolonged shellfish-harvesting bans due to blooms by Pyrodinium bahamense var. compressum severely affecting the fisheries industry in this area, as well as leading to Paralytic Shellfish Poisoning illnesses and fatalities. A novel integrated model was developed that mechanistically captures the interactions between hydrodynamic conditions, nutrients, the life history (cells and cysts) of Pyrodinium, as well as the cultured shellfish within the bay and their ensuing toxicities due to ingestion of toxic Pyrodinium cells and cysts. This is the second model developed for HABs in the Philippines, and the first to integrate different components of Pyrodinium bloom dynamics. The model is modularly composed of a watershed nutrient and diffusion model, a 3D hydrodynamic model, a Pyrodinium population model and a shellfish toxin model. It was able to capture the observed temporal variations of Pyrodinium and shellfish toxicity. It was also able to represent some aspects of the spatial distribution in Sorsogon Bay though there were discrepancies. To explore the dynamics of blooms, the linkages between the bloom and decline of the Pyrodinium population with shellfish toxicity as affected by temperature, salinity and nutrients were investigated. Comparisons with field results showed the seasonality of blooms in Sorsogon Bay is driven by increased rainfall. The timing of these conditions is important in facilitating Pyrodinium excystment and reproduction. Model results showed as well the potential significance of shellfish grazing and dinoflagellate cell mortality in influencing the decline of the bloom, and toxicity levels. This approach is promising in helping to understand mechanisms for HABs more holistically, and the model can be further improved to provide more precise quantitative information.

I-C-SEA Change: A participatory tool for rapid assessment of vulnerability of tropical coastal communities to climate change impacts.

We present a synoptic, participatory vulnerability assessment tool to help identify the likely impacts of climate change and human activity in coastal areas and begin discussions among stakeholders on the coping and adaptation measures necessary to minimize these impacts. Vulnerability assessment tools are most needed in the tropical Indo-Pacific, where burgeoning populations and inequitable economic growth place even greater burdens on natural resources and support ecosystems. The Integrated Coastal Sensitivity, Exposure, and Adaptive Capacity for Climate Change (I-C-SEA Change) tool is built around a series of scoring rubrics to guide non-specialists in assigning scores to the sensitivity and adaptive capacity components of vulnerability, particularly for coral reef, seagrass, and mangrove habitats, along with fisheries and coastal integrity. These scores are then weighed against threat or exposure to climate-related impacts such as marine flooding and erosion. The tool provides opportunities for learning by engaging more stakeholders in participatory planning and group decision-making. It also allows for information to be collated and processed during a "town-hall" meeting, facilitating further discussion, data validation, and even interactive scenario building.

Massive and acute hemoperitoneum due to rupture of the uterine artery by erosion from an endometriotic lesion.

OBJECTIVE: To report a case of acute hemoperitoneum due to erosion of the uterine artery by an endometriotic lesion of the left ovary. DESIGN: Case report and review of literature. SETTING: University medical center. PATIENT(S): A 39-year-old nulliparous woman with stage 3 endometriosis. INTERVENTION(S): Operative laparoscopy followed by laparotomy, oophorectomy, and ligation of the bleeding uterine artery. RESULT(S): Patient is fully recovered and is attempting to conceive. CONCLUSION(S): An endometriotic lesion eroded the wall of the uterine artery, causing massive, acute hemoperitoneum. Such an event may be overlooked during laparotomy and attributed to the trauma of surgery.

Remote sensing of coral reefs and their physical environment.

There has been a vast improvement in access to remotely sensed data in just a few recent years. This revolution of information is the result of heavy investment in new technology by governments and industry, rapid developments in computing power and storage, and easy dissemination of data over the internet. Today, remotely sensed data are available to virtually anyone with a desktop computer. Here, we review the status of one of the most popular areas of marine remote sensing research: coral reefs. Previous reviews have focused on the ability of remote sensing to map the structure and habitat composition of coral reefs, but have neglected to consider the physical environment in which reefs occur. We provide a holistic review of what can, might, and cannot be mapped using remote sensing at this time. We cover aspects of reef structure and health but also discuss the diversity of physical environmental data such as temperature, winds, solar radiation and water quality. There have been numerous recent advances in the remote sensing of reefs and we hope that this paper enhances awareness of the diverse data sources available, and helps practitioners identify realistic objectives for remote sensing in coral reef areas.

[Perforanting ocular trauma--comparative study]. / Traumatisme oculare perforante--studiu comparativ.

THE PURPOSE: Is the comparative study of surgically solved ocular trauma, within TARGOVISTE and BRASOV county Hospitals. MATERIAL AND METHOD: A retrospective study has been carried out, over a group of 234 patients, analysing comparatively their age, sex, environment background, occurrence circumstances and year season. RESULTS: The dominance of male patients can be remarked; according to their age, the dominance is between 40 and 55; according to the time period, the greater occurrence is between october and december. CONCLUSIONS: The study stresses out the similarity between the two groups (from BRASOV and TARGOVISTE): a greater occurrence of the male patients, the dominance of the perforant injuries of occular globe, the most affected age range is between 40 and 55.

Novel high-throughput polymer biocompatibility screening designed for SAR (structure-activity relationship): application for evaluating polymer coatings for cardiovascular drug-eluting stents.

The development of stents has been a major advancement over balloon angioplasty, improving vessel revascularization in obstructive coronary artery disease. The development of drug-eluting stents (DES) was the next breakthrough, designed to prevent the development of neointimal hyperplasia (restenosis) following percutaneous coronary interventions (PCI). Several DES are currently in various stages of clinical development; these DES use different stent platforms, different antiproliferative drugs and different polymeric coatings that carry the drugs and control their delivery kinetics. Following DES implantation, when the entire drug is released, the polymeric coating is still retained on the stent and can influence subsequent tissue response and vascular healing. Therefore, the biocompatibility of the polymeric coatings is an important component of DES safety and needs to be thoroughly evaluated. Here we describe the development of a high-throughput screening platform for the evaluation of polymer biocompatibility, assaying whether a polymeric coating triggers inflammation in vascular cells. The data generated by these assays provides a structure-activity relationship (SAR) that can guide polymer chemists in polymer design. We have also applied this methodology to evaluate the components of a novel polymer system (BioLinx polymer system) designed in-house. In addition, we assayed other polymeric coatings similar to those currently used on various DES. The results of this evaluation reveal a remarkable correlation between polymer hydrophobicity and its ability to provoke inflammatory response.