Artykuły w czasopismach na temat „Interval type-2 FNN”

As a key technology for highly reliable communication in the fifth generation mobile communication for railway (5G-R) high-speed railway wireless communication system, once the handover fails, it will pose a serious risk to the safe operation of high-speed railway. As the speed of high-speed trains continues to increase, the handover will become more frequent, and how to improve the success rate of the handover is a key problem that needs to be solved. In this paper, we proposed an optimization algorithm based on the interval type 2 feature selection recurrent fuzzy neural network (T2RFS-FNN), which is a recurrent fuzzy neural network with interval type 2 feature selection, to address the problem of fixed hysteresis threshold and single consideration for the handover algorithm between the control plane and the user plane of the high-speed railway under 5G-R. The algorithm integrates reference signal receiving power (RSRP). Reference signal receiving quality (RSRQ) and throughput to optimise the hysteresis threshold. First, a feedforward neural network structure is designed to implement fuzzy logic inference, and an interval type-two Gaussian subordination function is used to improve the nonlinear expressiveness of the model. Then, a feature selection layer is added to determine the output of the affiliation function, which completes the optimization of the hysteresis threshold and overcomes the drawback of the fixed hysteresis threshold of the handover algorithm. Finally, simulation analysis of the control-plane and user-plane handover algorithms is carried out separately. The results show that the proposed method can effectively improve the success rate and reduce the ping-pong handover rate compared to the comparison algorithms. The results provide a theoretical reference for the speedup of high-speed railway trains and the evolution of the global system for mobile communications for railway (GSM-R) to 5G-R.

Dictyosporium wuyiense, a new anamorphic fungus collected on a dead branch of bamboo in Tongmugou, Wuyi Mountain, China, is described and illustrated. It is characterised by being cheiroid, septate, complanate, and yellow, with two types of conidia composed mostly of five parallel compact rows of cells, sometimes with variable hyaline apical vesical appendages. Type 1 conidia are longer and the three central rows are protruding with swollen apical cells; type 2 conidia are wider and fan-shaped, with rows of apical cells approximately the same length. The conidial morphology on potato dextrose agar plates was variable, most with 2–3 vesical appendages. In phylogenetic analyses of the internal transcribed spacer (ITS) of rDNA, Dictyosporium wuyiense clustered with most Dictyosporium species in Dictyosporiaceae, but was a distinct species. Both morphological and molecular evidence support its description as a new species. A brief review of Dictyosporium and allied species is provided.

On the basis of small axial fan with five blades, 6 types of small axial flow fans with different chord lengths splitter blades were designed. Numerical simulation of 6 fan models with splitter blades and prototype fan were done by using Fluent. Based on the obtained simulation results, internal flow characteristics and aerodynamic noise were analyzed and compared. It indicates that: splitter blades with suitable chord length have improved significantly on internal flow characteristics, which inhibits backflow from pressure surface to the suction surface at blade tip and leading edge and restrains flow separation. The 6 model fans are better than prototype fan on aerodynamic noise improvement, but too long or too short chord lengths are both disadvantage to improve aerodynamic noise. The results reveal that 2/6, 3/6 and 4/6 chord length model have relatively better acoustic characteristics and internal flow characteristics. The research program will offer a reference for structural improvements and noise reduction on small axial flow fan.

AbstractObjectiveThis study aimed to identify the influence of predisposing, enabling, and reinforcing factors and the adherence to medication behavior among tuberculosis patients in Selogiri Wonogiri Public Health Center.MethodsThis study employed a descriptive cross-sectional research design. A questionnaire was used to collect primary data. Secondary data were obtained from patient treatment cards (Form TB 01). This research was carried out at Selogiri Health Center from November to December 2017. The participants were patients, both new and old patients, who had completed their treatment in the last 2 months or more, recorded from January 2016 to December 2017. A total sampling technique was used in this study. Logistic regression analysis was used to analyze the influence of predisposing, enabling, and reinforcing factors and the adherence to medication among tuberculosis patients.ResultsThe results of logistic regression analysis indicated that there were four independent variables that have a significant relationship with treatment variables, namely education (odds ratio (OR) = 0.025; 95% confidence interval (CI) = 0.001–0.039); knowledge (OR = 3.37; 95% CI = 0.19–57.71); type of drug (OR = 0.448; 95% CI = 0.012–16.07), and means of transportation (OR = 25.77; 95% CI = 1.33–500.47).ConclusionsEducation, knowledge, type of drug, and means of transportation influence medication compliance among tuberculosis patients. Therefore, supporting patients during medication program of tuberculosis is needed to improve their adherence medication during multidrug therapy.

Abstract Background Detailed histological evaluation is important in the diagnosis of autoimmune pancreatitis (AIP). However, it remains challenging to obtain adequate tissue from the pancreas. Recently, several reports have suggested the usefulness of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using the new “core” needles for acquiring pancreatic tissue. We aimed to investigate the usefulness of EUS-FNB for diagnosing AIP with one such needle, a 22-gauge Franseen needle. Methods Patients who met the imaging diagnostic criteria for AIP based on the International Consensus Diagnostic Criteria (ICDC) were enrolled in the study. All patients underwent EUS-FNB with a 22-gauge Franseen needle. Histological findings were evaluated based on the ICDC, and the detection rates of level 1 and level 1 or 2 histology were calculated. Results 56 patients from 11 different institutions were enrolled in the final analysis (55 suspected to have type 1 AIP and one with type 2 AIP). Lymphoplasmacytic infiltration, obliterative phlebitis, storiform fibrosis, and > 10 IgG4-positive cells per high-power field were detected in 55 (100 %), 24 (43.6 %), 40 (72.7 %), and 36 (65.5 %) of the 55 patients, respectively. The detection rates of level 1 and level 1 or 2 histology for AIP were 58.2 % (95 % confidence interval [CI] 44.1 % – 71.3 %) and 92.7 % (95 %CI 82.4 % – 98.0 %), respectively, which were apparently higher than our historical results (7.9 % [95 %CI 1.7 % – 21.4 %] and 62.2 % [95 %CI 46.5 % – 76.2 %], respectively) using a conventional needle. Conclusions EUS-FNB with a 22-gauge Franseen needle demonstrated favorable detection rates which would be clinically beneficial for the histological diagnosis of AIP.

ABSTRACT - Paraguay Belt occupies the western portion of the Tocantins Province, surrounding the Southeast of the Amazonian Craton and the eastern border of the Rio Apa Block, suggesting continuity with Tucavaca Belt in Bolivia. The rocks of the Paraguay belt were initially deposited in a glaciomarine environment in sites proximal to the cratonic area and deeper marine under the influence of turbidite flows in distal sites (Cuiabá Group, Bauxi and Puga Formation). The cap carbonates, thick limestone and dolostone succession of the Araras Group and siltstones and diamictites of the Serra Azul Formation related to Glaskiers glaciation overlay these diamictites (related to Marinoan glaciation). On the top there are terrigenous sediments of the Alto Paraguay Group, represented by sandstones of Raizama and claystones of Diamantino formations, respectively. The belt can be divided into three distinct structural zones: The Internal Domain is comprised of turbidite and glaciogenic sequences. Glaciogenic rocks on the base and carbonaceous and terrigenous sediments on the top occur in the External Domain. Horizontal platformal cover on the Amazonian Craton rocks are characterized by open folds. Structural studies allowed characterization of continuous deformational phases: the main deformational phase generated regional inverse folds with a NE-SW trend and fan geometry. Several regionally widespread lode-type gold deposits related to four types of the quartz veins were identified: type 1 is in concordance to bedding, type 2 is parallel to Sn, type 3 is parallel to Sn+2, and vertical Type 4 (Au-rich) is orthogonal to Sn. Late deformation developed in the Cuiabá region, recorded the closure of the ocean and the invertion where the hydrothermal fluids are the responsible for the orebodies formation. Keywords: Paraguay Belt, Structural, Stratigraphy, Metalogenesis.

Abstract Background: Although an internal tandem duplication (ITD) of the Fms-like receptor tyrosine kinase 3 receptor (FLT3) confers a very poor prognosis in acute myeloid leukemia (AML), it is insufficient to cause AML, suggesting important cooperating genetic events. NFATc1 is a member of the nuclear factor of activated T-cells (NFAT) transcription factor family, whose activation is dependent on nuclear translocation. NFATc1 is well known for its central role in regulating T-cell development and function, but was also shown to contribute to neoplastic transformation in diverse types of cancers. We have recently demonstrated that NFATc1 is overexpressed in primary FLT3-ITD+ AML causing resistance to the FLT3-kinase inhibitor sorafenib in vitro. Here we asked, whether NFATc1 induces AML transformation and drug resistance when expressed in the context of FLT3-ITD+ in vivo. Methods: Using the stem cell like (SCL)-promoter, Cre-recombinase inducible expression of a constitutively nuclear NFATc1 protein (cnNFATc1) was targeted to the early hematopoietic stem cell compartment. The SCL-Cre/cnNFATc1 mice were subsequently crossed with transgenic FLT3-ITD mice to yield Scl-Cre+/-/cnNFATc1+/+/FLT3-ITD+/+ mice (FCN+/+), which co-express cnNFAT and FLT3-ITD in the stem cell compartment. Results: Whereas FLT3-ITD mice developed a non-lethal, mild myeloproliferative disease, co-expression of FLT3-ITD with cnNFATc1 led to rapidly fatal AML. The median survival of FCN mice was only four months (range, 2 to 8 ). In median, FCN mice had 15-fold (range, 10 to 20) increased white blood cell count, a high proportion of circulating peripheral blasts, severe anemia and thrombocytopenia. There was also a significant B-cell developmental block. As opposed to F+/+ animals, FCN+/+ mice revealed a severe spleno- and hepatomegaly secondary to a gross leukemic infiltration, which disrupted the normal anatomical architecture of the involved organs. Fluorescence activating cell sorting and colony forming unit (CFU) assays demonstrated that cnNFATc1, when expressed in the context of FLT3-ITD, leads to a significant expansion of the lin-Sca+c-kit+ (LSK) stem cell-, progenitor cell (LK)-, the Gr-1-/CD11b+ monocytic and Gr-1low/CD11b+ immature myeloid compartments in bone marrow and spleen. FCN+/+-AML was polyclonal, and re-transplantable in secondary wild-type recipient mice. In vivo, cnNFATc1 caused not only potent FLT3-ITD inhibitor resistance to sorafenib and to the more FLT3-ITD-selective compound quizartinib, but also to chemotherapy. Comparative mRNA-sequencing of sorted LK and LSK compartments in wild-type, F+/+, C+/- N+/+, and FCN+/+ mice will reveal the genetic basis of the biological cooperativity between NFATc1 and FLT3-ITD in stem and progenitor cell compartments. Consistent with the murine data, a data set of AML patients (n=163) revealed that NFATc1 overexpression alone or when combined with FLT3-overexpression was associated with a significantly decreased overall survival (hazard ratio [HR] 1.91, CI 1.29-2.18, p=0.001 versus HR 2.57, CI 1.62-4.08, p<0.0001). Conclusions: These results provide for the first time evidence for an important role of nuclear NFATc1 overexpression in the molecular pathogenesis of FLT3-ITD positive AML and the induction of drug resistance. These data also underscore that the mutational landscape in AML insufficiently describes AML biology. Disclosures No relevant conflicts of interest to declare.

Abstract Selected pesticides were evaluated for phytotoxicity on 30 species and cultivars of containerized woody plants at a nursery in Madison, Ohio. A CO2 compression sprayer operating at 20 psi with a single Teejet SS8004 flat-fan nozzle was used to deliver 3785 ml finished spray to a total of 90 plants (Morestan 4F, 0.5 lb (AL7100 gal; Murphy oil soap, 4%; or water). This volume achieved application to run-off. Each treatment was applied to 3 plants of each plant type. All plants received 2 applications at 15-d intervals. Conditions for both applications (20 Aug and 4 Sep) were sunny skies, 21-24°C, and 0-10 km/h breeze. A second group of plants consisting of 17 species growing in field liner beds near Perry, Ohio, was used to evaluate potential phytotoxicity of Murphy soap (4%). Plants received 2 applications at 10-d intervals. Conditions on both dates (31 Aug and 10 Sep) were sunny skies, 21-24°C, and 10-16 km/h breeze. A 1-m section of each liner bed was sprayed with each treatment. Plants were inspected for symptoms of phytotoxicity 4, 10, and 29 Sep and 13 Oct.

Objective - The paper aims to measure tax incentive effectiveness specifically for SMEs using internal government factors such as modernization and socialization of the tax system and internal personal taxpayers' factors using tax knowledge. Methodology/Technique – Using primary data collected by questionnaire. Respondent criteria prepare according to SMEs classification from the Regulation of the Minister of Finance of the Republic of Indonesia. Data in this study were analyzed using multiple linear regression with SPSS statistics. Findings - this research found that modernization, socialization, and taxpayer knowledge will improve tax incentive efficiency. Internal government factors consist of modernization of the tax system and frequent socialization, significantly encouraging taxpayers to utilize the incentive without having deep knowledge of taxation. Novelty - This study explains the determinants of tax incentives from both sides, government, and taxpayer, especially for SMEs during pandemic COVID 19 in the Indonesian market. Type of Paper: Empirical. JEL Classification: E62, E64, H25, D83 Keywords: Tax Incentive, Fiscal Policy, Covid-19, Indonesia Reference to this paper should be referred to as follows: Diana, P; Eforis, C. (2022). The Determinants of Tax Incentive Effectiveness During Covid-19 Pandemic, Acc. Fin. Review, 7(2), 79 – 87. https://doi.org/10.35609/afr.2022.7.2(1)

The combined solar and mechanical dryer was constructed to use solar energy and electrical energy either separately or in combination to conduct air drying. There was various arrangement of drying condition for mechanical drying system such as using either 1KH-1F or 1KH-2F or 2KH-1F or 2KH-2F. While for solar drying either no fan or one fan or two fans were used. Different drying conditions were applied by changing the heating source and flow of air. The highest temperature was obtained in 2KH-1F condition for mechanical drying and convection gives highest temperature among different solar drying alternatives. The temperature in upper shelf for different solar operational condition ranged from 1.53 to 1.67 times of ambient temperature (25°C- 31°C) at peak time and 1.28 to 1.36 for lower shelf. The air velocity was 0.35 m/sec and 0.70 m/sec for 1-fan and 2-fan respectively.The performance of dryer was evaluated by drying potato slices having thickness 3, 5 and 7 mm. In both methods, drying rate increases with the increasing temperature and decreases with the increasing slice thickness following the power law equation. The values for the index ‘n’ of the power law equation are less than 2 (range from 0.53 to 1.42) for all the conditions, this indicating that external resistance to mass transfer was significant and internal resistance to mass transfer did not control the drying process under the given conditions. The effect of temperature on Diffusion co-efficient (De) follows Arrhenius type relationship. While analyzing the effect of temperature, the maximum activation energy for diffusion of water from Potato (7 mm thick slices, at upper shelf) was found to be 7.656 Kcal/g-mole and 8.252Kcal/g-mole for mechanical and solar conditions respectively.DOI: http://dx.doi.org/10.3329/jesnr.v4i2.10132J. Environ. Sci. & Natural Resources, 4(2): 35-40, 2011

Leptobrachella petrops (Rowley, Dau, Hoang, Le, Cutajar et Nguyen, 2017) was recently described from northern Vietnam. The tadpoles of this endemic species were collected for the first time from its type locality in Cham Chu Nature Reserve, Tuyen Quang Province. Taxonomic identification was based on a fragment of 16S rRNA gene of the newly collected tadpole and sequences of the type series obtained from GenBank. Morphological characters of the tadpoles (Gosner stages 25, 28, 35, 36, 43, 44, and 45) are as follows: Size medium, body elliptical, elongated, eyes are dorsolateral, narial apertures with characteristic gently rounded rims, slightly lifted above body surface, breathing hole on the left, vent tube dextral, separated from body and attached to lower fin, tail length exceeding two times body length, both upper and lower tail fins reach maximum height in posterior third, tip of tail pointed; dorsal surface olive-brown with distinct whitish-golden specklings, the tail has large black spots, ventral surface opaque-white, internal gills distinctly reddish. LTRF: 4(2 – 4)/3(1 – 2). In addition, we compare the tadpoles of Leptobrachella petrops with those of other species in the genus Leptobrachella.

Main Recommendations 1 ESGE recommends endoscopic ultrasonography (EUS) as the best tool to characterize subepithelial lesion (SEL) features (size, location, originating layer, echogenicity, shape), but EUS alone is not able to distinguish among all types of SEL.Strong recommendation, moderate quality evidence. 2 ESGE suggests providing tissue diagnosis for all SELs with features suggestive of gastrointestinal stromal tumor (GIST) if they are of size > 20 mm, or have high risk stigmata, or require surgical resection or oncological treatment.Weak recommendation, very low quality evidence. 3 ESGE recommends EUS-guided fine-needle biopsy (EUS-FNB) or mucosal incision-assisted biopsy (MIAB) equally for tissue diagnosis of SELs ≥ 20 mm in size.Strong recommendation, moderate quality evidence. 4 ESGE recommends against surveillance of asymptomatic gastrointestinal (GI) tract leiomyomas, lipomas, heterotopic pancreas, granular cell tumors, schwannomas, and glomus tumors, if the diagnosis is clear.Strong recommendation, moderate quality evidence. 5 ESGE suggests surveillance of asymptomatic esophageal and gastric SELs without definite diagnosis, with esophagogastroduodenoscopy (EGD) at 3–6 months, and then at 2–3-year intervals for lesions < 10 mm in size, and at 1–2-year intervals for lesions 10–20 mm in size. For asymptomatic SELs > 20 mm in size that are not resected, ESGE suggests surveillance with EGD plus EUS at 6 months and then at 6–12-month intervals.Weak recommendation, very low quality evidence. 6 ESGE recommends endoscopic resection for type 1 gastric neuroendocrine neoplasms (g-NENs) if they grow larger than 10 mm. The choice of resection technique should depend on size, depth of invasion, and location in the stomach.Strong recommendation, low quality evidence. 7 ESGE suggests considering removal of histologically proven gastric GISTs smaller than 20 mm as an alternative to surveillance. The decision to resect should be discussed in a multidisciplinary meeting. The choice of technique should depend on size, location, and local expertise.Weak recommendation, very low quality evidence. 8 ESGE suggests that, to avoid unnecessary follow-up, endoscopic resection is an option for gastric SELs smaller than 20 mm and of unknown histology after failure of attempts to obtain diagnosis.Weak recommendation, very low quality evidence. 9 ESGE recommends basing the surveillance strategy on the type and completeness of resection. After curative resection of benign SELs no follow-up is advised, except for type 1 gastric NEN for which surveillance at 1–2 years is advised.Strong recommendation, low quality evidence. 10 For lower or upper GI NEN with a positive or indeterminate margin at resection, ESGE recommends repeating endoscopy at 3–6 months and another attempt at endoscopic resection in the case of residual disease.Strong recommendation, low quality evidence.

Roughly two-thirds of ankle fractures are unimalleolar injuries, the Weber B-type fibula fracture being by far the most common type. Depending on the trauma and the accompanying soft-tissue injury, these fractures are either stable or unstable. Current clinical practice guidelines recommend surgical treatment for unstable Weber B-type fibula fractures. An ongoing randomized, parallel group, non-inferiority trial comparing surgery and non-operative treatment for unstable Weber B-type ankle fractures with allocation ratio 1:1. The rationale for non-inferiority design is as follows: By being able to prove non-inferiority of non-operative treatment, we would be able to avoid complications related to surgery. However, the primary concern related to non-operative treatment is increased risks of ankle mortise incongruency, leading to secondary surgery, early post-traumatic osteoarthritis and poor function. After providing informed consent, 126 patients aged 16 years or older with an unimalleolar Weber B-type unstable fibula fracture were randomly assigned to surgery (open reduction and internal fixation) or non-operative treatment (6-week cast immobilization). We have completed the patient enrolment and are currently in the final stages of the 2-year follow-up. The primary, non-inferiority outcome is the Olerud-Molander Ankle Score (OMAS) at 2 years (primary time point). The predefined non-inferiority margin is set at 8 OMAS points. Secondary outcomes include the Foot and Ankle Score, a 100 mm Visual Analogue Scale for function and pain, the RAND-36-Item Health Survey for health-related quality-of-life, the range-of-motion of the injured ankle, malunion (ankle joint incongruity) and fracture union. Treatment-related complications and harms; symptomatic non-unions, loss of congruity of the ankle joint, reoperations and wound infections will also be recorded. We hypothesize that non-operative treatment yields non-inferior functional outcome to surgery, the current standard treatment, with no increased risk of harms.

Abstract Background There is conflicting data and no clear consensus regarding the management of thyroid nodules 4 cm or larger. Diagnostic accuracy of fine needle aspiration (FNA) cytology of these nodules has been variable. Few studies have reported higher false negative rates suggesting surgery as reasonable option whereas other studies reported low false negative rates with no significant difference between small and large nodules. The goal of our study was to evaluate the reliability of FNA cytology in excluding malignancy in thyroid nodules 4 cm or larger in our patient population and to investigate the association between malignancy and any patient specific risk factors or ultrasound features. Methods We conducted a retrospective review of 380 patients with thyroid nodules who underwent thyroid surgery between 2014 and 2021 at our institution. Patient demographics such as age, gender and ethnicity, number and size of thyroid nodules, TSH level, FNA cytology, type of surgery and final surgical pathology results were recorded for patients with nodules 4 cm or larger and nodules between 2-4 cm. False negative rate of FNA cytology was compared between these two groups. Accessible ultrasound images for nodules 4 cm or larger were reviewed. Patient specific and nodule characteristics were compared between malignant and benign nodules. Fisher exact tests and multivariate logistic regression were used for data analysis. Results A total of 81 patients with thyroid nodules 4 cm or larger were studied, of which 22 patients (27.1%) had thyroid cancer. Mean age in patients with malignant nodules was 48.1 +/- 18.3 years versus 51.7 +/- 14.5 years in patients with benign nodules. The adjusted odds of malignancy for males was 20 times (95% CI: 3.3-125; p=0. 001) the odds for females. The adjusted odds of malignancy for nodules with both peripheral and internal vascularity on doppler ultrasound was 9.9 times (95% CI: 1.36-71.70; p=0. 024) that of nodules with only peripheral vascularity. Other nodule characteristics like composition, echogenicity, margins, halo, echogenic foci and taller than wide shape were not significantly different between malignant and benign nodules. False negative rate of FNA cytology for nodules 4 cm or larger was 8.7% (4/46 patients) as compared to 10% (4/40 patients) for nodules between 2-4 cm. This was not statistically significant (p=1. 0). Conclusion In our study, the false negative rate of FNA cytology in thyroid nodules 4 cm or larger was similar to that of nodules between 2-4 cm. This indicates that patients with thyroid nodules 4 cm or larger and benign cytology can be managed conservatively with appropriate clinical follow up. Male gender and nodules with peripheral and internal vascularity on doppler ultrasound were associated with thyroid malignancy in our review. Presentation: No date and time listed

This paper aims to numerically investigate the thermal enhancement of a latent thermal energy storage component with mini-channels as air passages. The investigated channels in two sizes of internal air passages (channel-1 with dh = 1.6 mm and channel-2 with dh = 2.3 mm) are oriented vertically in a cuboid of 0.15 × 0.15 × 0.1 m3 with RT22 as the PCM located in the shell. The phase change is simulated with a fixed inlet temperature of air, using ANSYS Fluent 19.5, with a varying number of channels and a ranging air flow rate entering the component. The results show that the phase change power of the LTES improves with by increasing the number of channels at the cost of a decrease in the storage capacity. Given a constant air flow rate, the increase in the heat transfer surface area of the increased number of channels dominates the heat transfer coefficient, thus increasing the mean heat transfer rate (UA). A comparison of the channels shows that the thermal performance depends largely on the area to volume ratio of the channels. The channel type two (channel-2) with a slightly higher area to volume ratio has a slightly higher charging/discharging power, as compared to channel type one (channel-1), at a similar PCM packing factor. Adding fins to channel-2, doubling the surface area, improves the mean UA values by 15–31% for the studied cases. The variation in the total air flow rate from 7 to 24 L/s is found to have a considerable influence, reducing the melting time by 41–53% and increasing the mean UA values within melting by 19–52% for a packing factor range of 77.4–86.8%. With the increase in the air flow rate, channel type two is found to have considerably lower pressure drops than channel type one, which can be attributed to its higher internal hydraulic diameter, making it superior in terms of achieving a relatively similar charging/discharging power in exchange for significantly lower fan power. Such designs can further be optimized in terms of pressure drop in future work, which should also include an experimental evaluation.

Early-aged children are individuals from 0 to 6 year old with unique characteristics and in the stage of growth and development, both physical and mental. Several aspects developed for their education include moral and religious values, social, emotional feelings, autonomy, language, cognitive, physical/motor skill, and art (Ramli, 2005, p.50). The development of these aspects affect each other, that is why it has to be optimally developed in every activity. One aspect of those basic skills should be developed in early-aged children is language. The objectives of this research are to describe (1) the quantity of Indonesian vocabularies in early-aged children; (2) certain Indonesian word classes in early-aged children; (3) certain scopes of Indonesian vocabularies in early-aged children; (4) Indonesian basic sentence pattern in early-aged children; (5) Indonesian basic sentence features considered by the form of integrative phrases; (6) Indonesian basic sentence features considered by the number of integrative phrases. The results of the research show that the vocabulary quantity of early-aged children varies due to external and internal factors. It triggers their inputs to vary from one to another. Word classes mastered by them include noun, verb, adjective, adverb, numeral, pronoun, and preposition. Based on the findings in the field, they have also mastered several vocabulary scopes, such as kinship, activity, place, number, color, universal objects, and animal types. In line with that, sentence patterns that have been mastered by them are FN-FV, FN1-FN2, FN-FA, FN-Num, and FN–FP.

Purpose. Analysis of methods to increase the efficiency of the cooling system of theAI-450M engine units of the Mi-2MSB helicopter and evaluation of gas-dynamic parameters at the impeller outlet, fan installation MI-2MSB Research methods: finite element method (FEM). Results. It was shown that the use of a centrifugal fan as the main element in the system of air injection, cabin air conditioning and cooling systems and engine units provide the following opportunities and improvements: - at constant speeds and without changes in the transmission system to increase the amount of running air by 200…300 %; - reduce the temperature of heated units to the values recommended by the operation manual; - to increase the service life of complex-loaded elements of the system of connection of free turbine shafts with the shaft of the main gearbox; - reduce the risk of accidents due to poor air conditioning in the cockpit and passenger seats. The analysis of possible types of C.S modernization was carried out, the estimated estimation of gas-dynamic parameters at the exit of the impeller - to the sub-radiator space was carried out. The problem was solved by changing the type of impeller from axial to centrifugal. Scientific novelty. The problem of creating an efficient and reliable cooling system for internal systems and units of the Mi-2MSB light multi-purpose aircraft, which has been modernized with the replacement of old GTD-350 engines with newer ones, AI-450 series - urgent, in the absence of similar light helicopters of domestic production. An important component of the safety and reliability of all components of the helicopter is to maintain the correct thermal regime of its components. Practical value. The obtained results are important in the further process of production and modernization of the Mi-2 helicopter of all modifications with the latest engines, as well as for helicopter development projects in Ukraine - SME-2 “Hope”, SME-6 “Otaman”, SME-8 and others. The ability to increase cooling efficiency, air conditioning and reduce engine load increases the life, reliability of components and improves comfort and performance for pilots and passengers.

Deep-sea fan development is generally thought to be controlled by a combination of changes in sea level, the shape and size of the basin in which the fans are growing, and the nature of the source area. The Early Miocene evolution of the eastern Mediterranean involved significant accumulation of deep-water clastic sediment in which the importance of each of these controlling factors can be evaluated. The deep-water clastic system located in the Adana Basin has been studied in detail. Two contemporaneous, small, radial, sand-rich submarine fans (one in the west and one in the east) exhibiting different scales, fan types and styles of deposition have been recognized within the Cingöz turbidite sequence of the northern Adana Basin in southern Turkey. Sedimentological studies indicate that the fans were controlled externally by tectonics and relative eustatic sea-level fall during late Serravallian time, in combination with the nature of the source area to the north. The internal architectural stacking patterns and external geometry of the two fan systems were strongly affected by the interaction of local tectonics and turbidity current pathways, including a major topographic confinement to the southeast that forced a vertical aggradation of the eastern fan and an east–west elongation of the western fan. This paper describes a classic example of a well-exposed deep-water clastic system where (1) tectonically driven sea-floor topography, (2) syn-sedimentary tectonism and (3) eustatic rise in sea level, are the primary controls on its development.

Background: Thyroid nodules are seen in 4-7% of the population which are more common in women. Excising all of these lesions is impractical and associated with certain risk factors as well. Fine needle aspiration (FNA) biopsy is the most relevant diagnostic procedure to decide those that need to be surgically excised or not. Methodology: The present study was conducted in Liban clinic, Mogadishu, Somalia. 220 patients whom were diagnosed with various types of tyroid lesions within 2 years of period were included in the study. Main objectives were to put forward the distribution of histological findings according to fine needle aspiration (FNA) biopsy results among different age groups, and to define the prevelance of certain subtypes of thyroid nodules in the region. Results: 207 patients had ‘benign’ nodules and 13 patients had ‘malignant’ nodules according histological evaluationof fine needle aspiration (FNA) biopsy results. ‘31-40’ years of age interval was found to have the highest percentage of histologically ‘benign findings’, while patients within ‘41-50’ years of age had the highest rate of ‘malignant lesions’ in count among the study population. ‘Papillary’ (n=8)(61.5%) and ‘medullary’ (n=5)(38.5%) carcinomas were most common malignant features.Mostly recorded benign lesions were ‘colloidal goiter, multinodular goiter (MNG), nodular hyperplasia and adenomatoid goiter’ (n=94)(45.4%). Conclusion: Characteristics of thyroidlesions in region of Mogadishu, Somalia show similar patterns based upon correlation of age with histological differences compared to recent literature. With the aid of FNA, majority of the population can be managed conservatively safely without need of surgical interventions. Bangladesh Journal of Medical Science Vol. 21(1) 2022 Page : 67-71

Four main unconformities (1–4) were recognized in the sedimentary record of the Cenozoic basins of the eastern External Betic Zone (SE, Spain). They are located at different stratigraphic levels, as follows: (1) Cretaceous-Paleogene boundary, even if this unconformity was also recorded at the early Paleocene (Murcia sector) and early Eocene (Alicante sector), (2) Eocene-Oligocene boundary, quite synchronous, in the whole considered area, (3) early Burdigalian, quite synchronous (recognized in the Murcia sector) and (4) Middle Tortonian (recognized in Murcia and Alicante sectors). These unconformities correspond to stratigraphic gaps of different temporal extensions and with different controls (tectonic or eustatic), which allowed recognizing minor sedimentary cycles in the Paleocene–Miocene time span. The Cenozoic marine sedimentation started over the oldest unconformity (i.e., the principal one), above the Mesozoic marine deposits. Paleocene-Eocene sedimentation shows numerous tectofacies (such as: turbidites, slumps, olistostromes, mega-olistostromes and pillow-beds) interpreted as related to an early, blind and deep-seated tectonic activity, acting in the more internal subdomains of the External Betic Zone as a result of the geodynamic processes related to the evolution of the westernmost branch of the Tethys. The second unconformity resulted from an Oligocene to Aquitanian sedimentary evolution in the Murcia Sector from marine realms to continental environments. This last time interval is characterized as the previous one by a gentle tectonic activity. On the other hand, the Miocene sedimentation was totally controlled by the development of superficial thrusts and/or strike-slip faults zones, both related to the regional geodynamic evolutionary framework linked to the Mediterranean opening. These strike-slip faults zones created subsidence areas (pull-apart basin-type) and affected the sedimentation lying above the third unconformity. By contrast, the subsidence areas were bounded by structural highs affected by thrusts and folds. After the third unconformity, the Burdigalian-Serravallian sedimentation occurred mainly in shallow- to deep-water marine environments (Tap Fm). During the Late Miocene, after the fourth unconformity, the activation of the strike-slip faults zones caused a shallow marine environment sedimentation in the Murcia sector and a continental (lacustrine and fluvial) deposition in the Alicante sector represented the latter, resulting in alluvial fan deposits. Furthermore, the location of these fans changed over time according to the activation of faults responsible for the tectonic rising of Triassic salt deposits, which fed the fan themselves.

To obtain well spread chromosomes, the cytogenetic protocol for Pangasianodon hypophthalmus and Clarias gariepinus were optimized. This includes, the colchicine concentration (0.01%, 0.025%, 0.05%)/exposure duration (1, 3, and 5 h), hypotonic solution (distilled water or 0.075M KCl solution)/exposure duration (30 min, 1, and 2 h), the time of cell suspension preparation (at hypotonic treatment or before slide preparation) and chromosome aging period (0, 3, and 7 days in Carnoy’s fixative). In addition, the type (i.e., fin, gill or kidney) and the amount of tissue (10, 50, 100 or 150 mg) were also investigated. Regardless of the species, the result obtained showed that well-spread chromosomes could be obtained using the following optimized protocol: Juveniles are injected with 0.05% colchicine (at one ml kg−1) and allowed to swim for 3 h. Then, 50 mg of gill tissue is made into cell suspension in 0.075M KCl for 1 h. The cell suspension is treated in Carnoy’s fixative (changed three times at 20 min interval) and then aged for 3 days. Finally, chromosome slides are made and stained with 10% Giemsa for 1 h.

An experimental study on pressure drop and heat transfer in single-phase was carried out using 10 types of internally helical-grooved and smooth small-diameter tubes with an outside diameter of 4 mm. The results are listed below: (1) In the turbulent flow region, fin height had the greatest effect, helix angle had only a minor effect, and the number of grooves had almost no effect upon the pressure drop versus the mass flow rate of the 4-mm grooved small-diameter tubes. In the laminar flow region, except for fin height, the shapes of the internal grooves had scarcely any effect upon pressure drop. (2) In the turbulent flow region, the heat transfer coefficients of the 4-mm grooved small-diameter tubes were greatly affected by fin height. The heat transfer coefficients became the maximum when a helix angle was near 15°, and there is a different tendency in the experiments of the pressure drop. On the other hand, there is almost no effect of the number of grooves. In the laminar flow region, there were no large differences in the heat transfer coefficients between the internally helical-grooved tubes and smooth small-diameter tube. (3) New empirical correlations for the friction factor and heat transfer coefficient in the laminar and turbulent flow regions were developed based on the experimental values. (4) The performance assessment in consideration of both heat transfer and pressure drop was indicated by using Colburn's analogy.

Control of seedling and rhizome johnsongrass [Sorghum halepense(L.) Pers. # SORHA] with five herbicides was evaluated after postemergence application in various diluents and spray volumes using one to three types of applicators from 1983 to 1985. The rate of each herbicide required to control seedling johnsongrass using paraffinic oil as the diluent in applications with an external- or internal-mixing air-assist sprayer at a spray volume of 9.4 L/ha was one-half the rate required when water plus 1.25% (v/v) paraffinic oil concentrate (POC) or water plus 1.25% (v/v) soybean oil concentrate (SOC) were the diluents in applications with a conventional sprayer equipped with fan jet spray nozzles at a spray volume of 187 L/ha. Rates were also reduced when once-refined soybean oil was the diluent at a spray volume of 9.4 L/ha, except for the ethyl ester of quizalofop {(±)-2-[4-[(6-chloro-2-quinoxalinyl)oxy] phenoxy] propanoic acid}. Sethoxydim {2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one} was equally effective on seedling johnsongrass growing in soybeans [Glycine max(L.) Merr. ‘DPL 105’] when applied at 224 g ai/ha with an internal-mixing air-assist sprayer or a controlled-droplet applicator (CDA) at a spray volume of 9.4 L/ha and a conventional sprayer at a spray volume of 187 L/ha, regardless of diluent. Conventional application required the use of 1.25% (v/v) SOC or POC as part of the diluent to be effective. For three of the five herbicides evaluated on rhizome johnsongrass, paraffinic oil at a spray volume of 9.4 L/ha was the only diluent that resulted in season-long control. Rhizome johnsongrass control with this diluent also resulted in significantly higher soybean yields than all other diluent-spray volume treatments.

Passive solar still is the simplest design for distilling seawater by harnessing solar energy. Although it is undeniable that solar still is a promising device to provide an additional freshwater source for global increasing water demand, low thermal efficiency along with daily distillate yield are its major disadvantages. A conventional solar still can produced 2 to 5 L/m2day. Various studies have been carried out to improve passive solar stills in terms of daily productivity, thermal efficiency, and economic effectiveness. Most of the researches that relate to the daily output improvement of passive solar still concentrates on enhancing evaporation or/and condensation processes. While the condensation process is influenced by wind velocity and characteristics of the condensed surface, the evaporation process is mainly affected by the temperature of basin water. Different parameters affect the brackish water temperature such as solar radiation, design parameters (for example water depth, insulators, basin liner absorptivity, reflectors, sun tracking system, etc). The inclined angle of the top cover is suggested to equal the latitude of the experimental place. Moreover, the decrease of water depth was obtained as a good operational parameter, however, the shallow water depth is required additional feed water for ensuring no dry spot existence. Reflectors and sun-tracking systems help solar still absorb as much solar intensity as possible. The internal reflector can enhance daily yield and efficiency of stepped solar still up to 75% and 56% respectively, whereas, passive solar still with the support of a sun-tracking system improved daily yield up to 22%. Despite large efforts to investigate the impact of the different parameters on passive solar distillation, the effect of the basin liner (including appropriate shapes and type of material), needs to be analyzed for improvement in practical utilization. The present work has reviewed the investigation of the solar still performance with various types of basin liner. The review of solar stills has been conducted critically with rectangular basin, fins basin, corrugated basin, wick type, steps shape, and cylindrical shape basin with variety of top cover shapes. The findings from this work conclude that the basin liner with a cylindrical shape had better performance in comparison with other metal types and provides higher freshwater output. Stepped type, inclined, fin absorber, and corrugated shapes had the efficient performance. Further exploration revealed that copper is the best-used material for the productivity of passive solar still.

(1) Background: Many schools and higher education settings have confronted the issue of reopening their facilities after the COVID-19 pandemic. In response, several airflow strategies spanning from adding portable air purifiers to major mechanical overhauls have been suggested to equip classrooms with what is necessary to provide a safe and reliable environment. Yet, there are many unknowns about specific contributions of the building system and its design and performance on indoor air quality (IAQ) improvements. (2) Methods: this study examined the combined effect of ventilation type, airflow rates, and filtration on IAQ in five different classrooms. Experiments were conducted by releasing inert surrogate particles into the classrooms and measuring the concentrations in various locations of the room. (3) Results: we showed that while the distribution of particles in the space is a complex function of space geometry and air distribution configurations, the average decay rate of contaminants is proportional to the number of air changes per hour in the room. (4) Conclusions: rooms with a central HVAC system responded quicker to an internal source of contamination than rooms with only fan coil units. Furthermore, increasing the ventilation rate without improved filtration is an inefficient use of energy.

Skeletal concentrations are common foci for paleontologic collecting, yet vary widely in their expected levels of taphonomic bias, particularly temporal resolution and biological fidelity. Basic concentration types include: (1) simple event-concentrations composed of anything from autochthonous-census, entirely exotic, or entirely remanié assemblages (e.g., shelly tempestites, shell-lined burrows); (2) composite concentrations of many stacked to complexly amalgamated events, accumulated in normal to expanded thickness (e.g., bioherms, shell banks & fans); (3) stratigraphically condensed hiatal concentrations having an even greater minimum degree of assemblage-level taphonomic bias (e.g., transgressive shelly sands, sediment-starved bone beds); and (4) lag-concentrations formed by erosion/corrosion of significant section and composed typically of highly culled and time-disordered skeletal material. Detailed field study of three temperate to subtropical basins in North America and reconnaissance of other basins at similar and lower paleolatitudes indicate that these four concentration types are distributed systematically within unconformity-bounded sequences and, moreover, that marine sequences vary qualitatively both in their stratigraphic anatomy (e.g. Van Wagoner et al., 1990; Einsele & Bayer, 1991) and skeletal taphonomy as a function of long-term subsidence.I. Basins of moderate subsidence (total 10's cm/ka maintained over 1–10 ma) are characterized by “textbook” sequences composed of discrete upward-shallowing parasequences in transgressive and highstand/regressive marine phases. Taphonomically, sequences in these settings typically contain a variety of concentration types, and therefore require careful taphonomic differentiation. In the shale-rich Cretaceous Ostracode Zone (Alberta foreland basin; Banerjee & Kidwell, 1991), for example, composite shell beds mark the tops of parasequences near the basin margin, event-beds of granulated shell mark the bases of parasequences further offshore, and diagenetically complex, shell-poor hiatal limestones mark maximum flooding surfaces in the most distal areas.II. Basins of high subsidence (total 100's cm/ka maintained over ≥1ma) are typically characterized by expanded sequences with vague parasequences; sedimentary cyclicity is linked more clearly to local tectonism and autocyclic environments than to eustasy. Taphonomically, these records are dominated by comparatively straightforward event- and composite concentrations. In the Mio-Pliocene Salton Trough (Gulf of California rift basin), for example, oyster bioherms and shell-ridges cap upward-shallowing delta-front cycles, and coral-bearing bioclastites occur along the distal toes of coastal alluvial fans and are banked against inter-fan rocky shorelines. Hiatal concentrations are poorly developed, even along downlap surfaces, and laterally extensive lags are rare.III. Basins of low subsidence (total ≤ few cm/ka maintained over 1–10 ma) are characterized by stratigraphically telescoped sequences with poorly developed (and locally deepening-up) “parasequences”; transgressive surfaces largely coincide with sequence boundaries. Hiatal and lag concentrations are relatively common and close-spaced stratigraphically; these may be taxonomically diverse even in temperate latitudes owing to environmental condensation, and in all instances are taphonomically complex. In the Miocene Chesapeake Group (outcropping U.S. Altantic passive margin), 4 transgressive hiatal shell concentrations lie within 40 m of section; each contains up to ~100 species and rests directly on a 3rd-order sequence boundary. A starved hiatal bone bed with high microplankton diversity marks the major 2nd-order downlap surface; lags of comminuted bones, teeth, and mollusk steinkerns mantle shallow-water unconformities near lap-out.

Abstract 'Sanibel' variety cabbage was planted 7 Oct into double-row beds with 40-inch centers at the Hoblitzelle Research and Demonstration Farm, Mercedes, Tex. Soil type was an Hidalgo sandy clay loam. Plants were thinned to a 6-inch spacing on 1 Nov, and 60 lb N-32 fertilizer was side-dressed on 3 Dec. Two separate experiments were conducted, one to evaluate efficacy of foliar-applied insecticides, and one to evaluate side-dressed insecticides for control of poplar petiole gall aphids (cabbage root aphids). Experimental design for both tests was a randomized complete block with 4 replications. The plots measured 2 beds by 30 ft (foliar test) or 4 beds by 30 ft (side-dress test) with a buffer row between plots. Side-dress treatments were applied on 3 Dec, and foliar sprays were begun 24 Dec. The RH-7988-treated plot received 1 foliar application, the other 2 insecticides were sprayed twice at a 7-day interval. Soil injections were applied with a liquid fertilizer applicator, and foliar sprays were discharged through a COzpowered, backpack sprayer calibrated to spray 10 gal/acre (30 psi, 4 flat-fan nozzles per plot). Efficacy was evaluated by removing the roots of 4 plants from each plot and washing them in 1 gal of water containing 1 tablespoon of CaCl. Dislodged aphids were counted as they floated to the surface of the water. Cabbage heads were harvested on 13 ft, 2 inches of row per plot to determine yield. Data were analyzed for treatment differences with ANOVA, and means were separated with Duncan's New Multiple Range Test.

Fertilizer applications has been widely utilized to improve soil fertility, and consequently enhanced plant productivity. Yet, the best fertilizer type for late rainy season forage production is rarely tested in Nigeria. Hence, an experiment was conducted to investigate the regrowth potential of two tropical grasses during late rainy season in Abeokuta, derived Savanna zone of Nigeria. This experiment comprised four fertilizer treatments [Nitrogen Phosphorous Potassium 20: 10: 10 fertilizer (NPK), Aleshinloye organo-mineral fertilizer (AOM), Poultry manure (PM), no fertilizer (control)] and two grass species (Panicum maximum var Ntchisi and Andropogon tectorum). This experiment was a 4 × 2 factorial arrangement laid out in a split plot design, forming 8 treatments that were replicated three times. Data were collected on agronomic parameters such as plant height (PH), plant length (PL), leaf length (LL), leaf width (LW), number of tillers/stand (TN) and number of leaves/stand (NL) for the period of 6 weeks after cutback at an interval of 2 weeks. The results revealed that NPK fertilized P. maximum var Ntchisi had higher LLthan others. In the case of TN and NL, fertilized P. maximum var Ntchisi performed better than other grass. Poultry manure fertilized P. maximum var Ntchisi gave a greater TN and NL in relation to other treatments group. Therefore, it could be concluded that P. maximum var Ntchisi fertilized with NPK and PM fertilizers had better regrowth performance during the late rainy season in Abeokuta. For high pasture productivity during dry season, P. maximum var Ntchisi fertilized with Poultry manure fertilizer should be adopted by farmers. Les applications d'engrais ont été largement utilisées pour améliorer la fertilité des sols et, par conséquent, une productivité des plantes améliorée. Pourtant, le meilleur type d'engrais pour la production de forage de la saison des pluies tardifs est rarement testé au Nigéria. Par conséquent, une expérience a été menée pour enquêter sur le potentiel de repousse de deux herbes tropicales pendant la fin de la saison des pluies à Abeokuta, une zone de savane dérivée du Nigéria. Cette expérience comprenait quatre traitements d'engrais [Engrais de potassium de phosphore d'azote 20: 10: 10 (NPK), engrais organo-minéral Aleshinloye (EOA), fumier de volaille (FV), sans engrais (contrôle)] et deux espèces d'herbe (Panicum maximum var Ntchisi et andropogon tectorum). Cette expérience a été une disposition factorielle de 4 × 2 dans une conception de tracé divisée, formant 8 traitements reproduits trois fois. Les données ont été collectées sur des paramètres agronomiques tels que la hauteur de la plante (HP), la longueur de la plante (LP), la longueur des feuilles (LF), la largeur de la feuille (LF), le nombre de barreurs (NB) et le nombre de feuilles (NF) pour la période de 6 semaines après la réduction à un intervalle de 2 semaines. Les résultats ont révélé que la NPK Fertilisée P. Maximum Var ntchisi avait plus de LF que d'autres. Dans le cas de Nb et NF, P. Fertilisé Var ntchisi a fonctionné mieux que d'autres herbes. Licure de volaille Fertilisée P. maximum var ntchisi a donné un plus grand NB et NF par rapport à d'autres types de traitements. Par conséquent, on pourrait en conclure que P. Var ntchisi Fertilisé avec NPK et les engrais FVavaient une meilleure performance de repousse pendant la fin de la saison des pluies à Abeokuta. Pour une productivité élevée de pâturage pendant la saison sèche, P. Var ntchisi Fertilisé avec un engrais de fumier de volaille doit être adopté par des agriculteurs.

Introduction: The thyroid is an endocrine gland situated in the infrahyoid compartment of neck in a space outlined by muscle, trachea, esophagus, carotid arteries and jugular veins. Though nodular thyroid disease is relatively common, thyroid cancer is rare and accounts for less than 1% of all malignancies indicating that overwhelming majority of thyroid nodules are benign. The purpose of this study was to assess the sonographic characteristics in a solitary thyroid nodule and predict risk of malignancy.Methods: This prospective study was conducted in a tertiary care hospital in Kathmandu.62 patients with palpable thyroid nodule were evaluated for sonographic characteristics .USG guided FNA for cytopathological examination was then performed.Results: Out of 66 patients, four were subsequently excluded because they didn’t fulfill the inclusion criteria. Of the 62 patients, 47 (75.8%) were females and 15 (24.2%) were males. Among 56 benign nodules, 45 (80.4%) were in females and 11(19.6) were in male. Among 6 malignant nodules, 4(66.7%) were in males and 2 (33.3%) were in females. Result shows 5 malignant nodules (83.3%) were solid where as 1 malignant nodule (16.7%) was complex with solid predominance. All 4 cystic nodules (7.1%) were benign. All complex nodules with predomint cystic components were also benign. One malignant nodule (16.7%) had snow storm type of microcalcification. None of the benign nodules had microcalcification. Nodule having microcalcification was malignant. Findings showed that all malignant nodules (100%) had increased internal vascularity whereas benign nodules were variable in internal vascularity.Conclusion: This study has shown that colloid goiter is the commonest benign diagnosis whereas papillary carcinoma is the commonest malignancy. Malignant nodules are solid or predominantly solid whereas cystic and predominantly cystic nodules are likely to be benign. Macrocalcification and internal vascularity are not reliable to differentiate benign from malignant nodule. However, snowstorm calcification makes a nodule likely to be malignant whereas egg shell calcification is characteristic for benign nodule.

In this study, graphene is used as a photothermal material, which is added to the SiO2 superhydrophobic solution treated with fluorine silane, and then sprayed on the copper plate surface to prepare a new type of photothermal superhydrophobic surface with contact angles up to 160.5° and 159.8°. Under the conditions of natural convection, the effects of photothermal superhydrophobic surfaces on droplet condensation, freezing, and frost growth are investigated in different environments. The results show that the photothermal superhydrophobic surface can not only delay the freezing of surface droplets, prolong the freezing time of droplets, and reduce the thickness of the frost layer, but also allow for the rapid removal of droplets under near-infrared (NIR) irradiation. If the droplet is irradiated by an infrared laser emitter while the cooling system is still turned on, the internal temperature of the droplet will always be higher than the crystallization temperature under the illumination intensity of 2 W/cm2, and the droplets will not freeze. With the extension of irradiation time, the droplet will evaporate, and the volume of the droplet will decrease. On the basis of summarizing and evaluating the study on the anti-icing performance of superhydrophobic surfaces and the properties of photothermal materials, a new research direction regarding the anti-icing of fan blade surfaces was established. This kind of surface combines the photothermal capabilities of light absorption materials with the micro- and nanostructure of the superhydrophobic surface to improve the anti-icing capability of wind turbine blade surfaces in difficult conditions.

Abstract Pesticide spray drift represents an important exposure pathway that may cause illness among orchard workers. To strike a balance between improving spray coverage and reducing drift, new sprayer technologies are being marketed for use in modern tree canopies to replace conventional axial fan airblast (AFA) sprayers that have been used widely since the 1950s. We designed a series of spray trials that used mixed-effects modeling to compare tracer-based drift volume levels for old and new sprayer technologies in an orchard work environment. Building on a smaller study of 6 trials (168 tree rows) that collected polyester line drift samples (n = 270 measurements) suspended on 15 vertical masts downwind of an AFA sprayer application, this study included 9 additional comparison trials (252 tree rows; n = 405 measurements) for 2 airblast tower sprayers: the directed air tower (DAT) and the multi-headed fan tower (MFT). Field-based measurements at mid (26 m) and far (52 m) distances showed that the DAT and MFT sprayers had 4–15 and 35–37% less drift than the AFA. After controlling for downwind distance, sampling height, and wind speed, model results indicated that the MFT [−35%; 95% confidence interval (CI): −22 and −49%; P &lt; 0.001] significantly reduced drift levels compared to the AFA, but the DAT did not (−7%; 95% CI: −19 and 6%; P = 0.29). Tower sprayers appear to be a promising means by which to decrease drift levels through shorter nozzle-to-tree canopy distances and more horizontally directed aerosols that escape the tree canopy to a lesser extent. Substitution of these new technologies for AFA sprayers is likely to reduce the frequency and magnitude of pesticide drift exposures and associated illnesses. These findings, especially for the MFT, may fit United States Environmental Protection Agency’s Drift Reduction Technology (DRT) one-star rating of 25–50% reduction. An ‘AFA buyback’ incentive program could be developed to stimulate wider adoption of new drift-reducing spray technologies. However, improved sprayer technologies alone do not eliminate drift. Applicator training, including proper sprayer calibration and maintenance, and application exclusion zones (AEZs) can also contribute to minimizing the risks of drift exposure. With regard to testing DRTs and establishing AEZs, our study findings demonstrate the need to define the impact of airblast sprayer type, orchard architecture, sampling height, and wind speed.

Background:It is challenging to monitor treatment effects after intra-articular (IA) injection with tissue modifying drugs. Assessment of biomarker levels in synovial fluid may be one solution to the challenge. Sprifermin is a truncated form of fibroblast growth factor (FGF) 18 known to induce chondrocyte proliferation and type II collagen formation [1,2]. Data from preclinical investigations show that cartilage formation happens in different phases after therapy with sprifermin, starting with a phase of cartilage degradation during the induction of proliferation of chondrocytes followed by a phase of cartilage formation/production of extracellular matrix.Objectives:The aim was to investigate the effect of IA administrated sprifermin on cartilage turnover activity as compared to placebo in the injected joint by measurement of markers using longitudinal synovial fluid samples of patients participating in the FORWARD study.Methods:Each included patient had baseline and at least one FU sample available. Synovial fluid (SF) from participants receiving injections at three consecutive weeks in six month intervals through to week (wk) 80 (fig.A) available from the phase II clinical trial evaluating the efficacy and safety of intraarticularly delivered sprifermin [3] were selected for the investigations. Biochemical markers were measured in available SF samples of the placebo (containing saline IA, n=38) and the highest sprifermin dose group (100 mcg/IAx4, n=59). Samples were pretreated with ultrasound and centrifugation to decrease viscosity. Markers measured were PRO-C2 (type II collagen formation), huARGS (aggrecan degradation), and FBN-C (fibronectin). Markers are technically validated for synovial fluid measurement. Data were individually normalized to baseline to investigate the median proportional change over time.Results:Baseline mean (SD) levels of the markers in SF at BL were: PRO-C2, 21.4 (13.6) ng/mL, huARGS, 1117 (516) pM and FBN-C, 2556 (1959) ng/mL. PRO-C2 was initially decreased (from BL to wk 2) after injection with sprifermin; however, the level was increased at the beginning of each new injection cycle followed by a decrease after injection of sprifermin (Fig.B). Overall synovial PRO-C2 levels increased over time in therapy with sprifermin, while no change was observed for the placebo arm. huARGS showed a similar pattern as PRO-C2 – there was an overall increase in ARGS over time in the sprifermin group (fig.C). Interestingly ARGS continuously decreased over time in the placebo group. FBN-C is continuously increased after injection’s cycles, whereas no effect was seen in the placebo group (fig.D).Conclusion:Confirmatory of the preclinical investigations a biphasic response on cartilage turnover after injection with sprifermin was observed. Biochemical indications of cartilage formation and chondrocyte proliferation was only modulated in the sprifermin group, and cartilage degradation (ARGS) was temporal induced and reduced by sprifermin and placebo injections, respectively.References:[1]Gigout A, et al. “Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix”. Osteoarthr Cartil. 2017;25.[2]Reker D, et al. “Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo”. J Transl Med. 2017;15.[3]Hochberg MC, et al. “Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis”. JAMA. 2019; Oct 8;322(14).Disclosure of Interests:Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Angela Manginelli Employee of: Merck KGaA, Flavie Moreau Employee of: Merck KGaA, Yi He Employee of: YH is a full time employee of Nordic Bioscience A/S, Yunyun Luo Employee of: Nordic Bioscience A/S, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee of Nordic Bioscience., Asger Reinstrup Bihlet Shareholder of: Nordic Bioscience A/S., Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Hans Gühring Employee of: Merck KGaA, Christoph Ladel Employee of: Merck KGaA

Abstract. The frequency of debris flows is hypothesized to have increased in recent decades with enhanced rainstorm activity. Geological evidence to test the relationship between climate and debris flow activity for prehistoric times is scarce due to incomplete sediment records, complex stratigraphy, and insufficient age control, especially in Alpine environments. In lacustrine archives, the link between onshore debris flow processes and the sedimentary record in lakes is poorly investigated. We present an amphibious characterization of alluvial fan deltas and a continuous 4000-year debris flow record from Plansee (Tyrol, Austria), combining light detection and ranging (lidar) data, swath bathymetry, and sediment core analyses. The geomorphic investigation of two fan deltas in different developmental stages revealed an evolutionary pattern of backfilling and new channel formation onshore, together with active subaqueous progradation on a juvenile fan delta, major onshore sediment deposition, and only few, but larger, subaqueous deposits on a mature fan delta. Geomorphic evidence for stacked and braided debris flow lobes, subaquatic landslide deposits, and different types of turbidites in sediment cores facilitated a process-based event identification, i.e. distinguishing between debris-flow-induced or earthquake-induced turbidites throughout the 4000-year sedimentary record. We directly correlate subaqueous lobe-shaped deposits with high backscatter signals to terrestrial debris flow activity of the last century. Moreover, turbidite thickness distribution along a transect of four cores allows us to pinpoint numerous events as being related to debris flow activity on a juvenile fan delta. In the sediment core, debris-flow-induced turbidites feature a more gradual fining upward grain size trend and higher TOC (total organic carbon) and δ13C values compared to earthquake-induced turbidites. The 4000-year event record contains 138 debris-flow-induced turbidites separated into four phases of similar debris flow activity (df phases). df phase 1 (∼2120 to ∼2040 before the common era – BCE) reflects the second-highest observed event frequencies and is interpreted as being a postseismic landscape response. After a long period of long recurrence intervals without any outstanding increases in debris flow activity during df phase 2 (∼2040 BCE to ∼1520 common era – CE), there are slightly increased event frequencies in df phase 3 (∼1520 to ∼1920 CE). df phase 4 (∼1920 to 2018 CE) exhibits a drastic increase in debris flow activity, followed by the overall highest debris flow frequency of the whole record, which is about 7 times higher than during df phase 3. We show that the frequency increase in the debris-flow-induced turbidite record matches a previously postulated increase in debris flow events derived from aerial photography at Plansee in the last century. The triggering of debris flows is more controlled by short, intense precipitation than any other mass movement process, and we demonstrate that lacustrine debris flow records provide a unique inventory of hazard-relevant rainstorm frequencies over decades, centuries, and millennia. The presented increase in debris flow frequency since the start of the 20th century coincides with a twofold enhanced rainstorm activity in the Northern European Alps and, therefore, provides a novel technique for the systematic understanding of non-stationary debris flow frequencies in a changing climate.

1. Taste buds in catfish are found not only within the oropharyngeal cavity, as in mammals, but are also located along the external body surface of the animal from the barbels and lips to the caudal fin. Because these taste buds are innervated by the facial (cranial VII) nerve, the extraoral taste system of catfish is analogous to the mammalian taste system of the anterior two-thirds of the tongue, which contains taste buds innervated by the chorda tympani nerve, and of the soft palate and nasoincisor ducts, which contain taste buds innervated by the greater superficial petrosal nerve. 2. The majority of information concerning the specificity of individual taste fibers in vertebrates has been obtained primarily in mammals to stimuli representing the four basic human taste qualities (i.e., salty, sweet, sour, and bitter). In the present report, we examine the evidence for gustatory fiber types within the stimulus class of amino acids, compounds known to be especially relevant gustatory stimuli for catfish and other teleosts. 3. Action potentials were recorded from 60 individual facial taste neurons obtained from 28 sea catfish (Arius felis). Stimuli were 10(-4) M concentrations of L-alanine, D-alanine, glycine, L-proline, L-histidine, and L-arginine, compounds selected from an original stimulus list of 28 amino acids. Responses were quantified as the number of action potentials evoked at various time intervals from the first 0.5 s up to 10 s of response time. 4. The spontaneous activity of 42 fully characterized neurons was 0.8 +/- 2.1 SD spikes/3 s. The average rate of spike discharge increased 50-fold during stimulation with the most effective amino acid (42 +/- 31 spikes/3 s, mean +/- SD). The majority of the sampled neurons were not narrowly tuned to the amino acid stimulants tested (mean breadth of responsiveness, H = 0.60; range 0-0.95). 5. Hierarchical cluster analysis of the fully characterized neurons identified two large and two small groups of cells. The largest group (n = 22) of neurons was stimulated most by L-alanine and glycine; the other large group (n = 17) was stimulated most by D-alanine. For this latter group, the response to glycine was relatively low, whereas the responses to L-alanine varied from 0 to nearly 100% of the D-alanine response.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract Background: At a predefined interim analysis (IA), RATIONALE-303 (NCT03358875) demonstrated improved overall survival (OS) for TIS vs D in the intent-to-treat (ITT) population with a manageable safety profile. Given disease characteristics, standard of care treatment/prognosis differ between histologic types of NSCLC. Here we report the data on the sq population. Methods: 805 patients (pts) with histologically confirmed, advanced NSCLC with progressive disease during or after ≥ 1 platinum (Pt)-containing chemotherapy regimen were randomized (2:1) to TIS 200 mg IV or D 75 mg/m2 IV every 3 weeks until disease progression, intolerable toxicity, or withdrawal. Histology (sq vs non-sq), was a stratification factor for randomization. Dual primary endpoints were OS in the ITT and PD-L1 ≥ 25% populations. The IA was conducted after ~426 deaths (76% of planned events). Efficacy and safety were assessed in 370 randomized pts with sq histology. Results: Baseline characteristics of sq pts were balanced between treatment arms and similar to the ITT population. As of August 10, 2020, at median follow-up of 19.0 and 19.3 months (mo), respectively, median (95% CI) OS was longer with TIS (16.0 mo [13.8, 18.9]) vs D (11.3 mo [8.7, 12.7]) in the sq ITT population, and progression free survival (PFS), objective response rate (ORR) and duration of response (DoR) were also improved for TIS vs D (Table). 95.1% (TIS) and 99.1% (D) of pts had ≥ 1 treatment-emergent adverse event (TEAE) and 38.1% (TIS) and 79.5% (D) of pts had ≥ Grade 3 TEAEs. The most common TEAEs were anemia, cough and alanine amino transferase increased (TIS arm), and anemia, alopecia, and neutrophil count decreased (D arm). Conclusions: TIS prolonged OS with a favorable safety profile in pts with advanced sq NSCLC who progressed after a Pt-containing regimen. The data are consistent with the overall ITT population. Efficacy* TIS (n=248) D (n=122) Median OS, mo (95% CI) 16.0 (13.80, 18.86) 11.3 (8.67, 12.68) OS HR (95% CI)† 0.58 (0.436, 0.761) P &lt; 0.0001‡§ Median PFS, mo (95% CI) 6.2 (4.21, 6.37) 2.3 (2.10, 3.38) PFS HR (95% CI)† 0.45 (0.343, 0.577) P &lt; 0.0001‡§ ORR, n (%) 57 (23.0) 5 (4.1) Median DoR, mo (95% CI) 16.7 (8.31, NE) 6.2 (2.10, 8.31) Safety** TIS (n=247) D (n=117) TEAEs ≥ 20% of patients in either arm, n (%) All grades ≥ Grade 3 All grades ≥ Grade 3 Anemia 76 (30.8) 7 (2.8) 56 (47.9) 10 (8.5) Decreased appetite 41 (16.6) 2 (0.8) 33 (28.2) 3 (2.6) Asthenia 38 (15.4) 5 (2.0) 27 (23.1) 6 (5.1) White blood cell count decreased 12 (4.9) 1 (0.4) 32 (27.4) 21 (17.9) Leukopenia 9 (3.6) 1 (0.4) 31 (26.5) 19 (16.2) Neutrophil count decreased 7 (2.8) 2 (0.8) 42 (35.9) 35 (29.9) Alopecia 5 (2.0) 0 (0.0) 52 (44.4) 0 (0.0) Neutropenia 2 (0.8) 0 (0.0) 37 (31.6) 34 (29.1) *Efficacy analysis set - Sq patients; †Stratified; ‡One-sided stratified log-rank test; §Descriptive P-value; **Safety analysis set - Sq patients CI; confidence interval; D, docetaxel; DoR, duration of response; HR, hazard ratio; mo, months; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; sq, squamous; TEAE, treatment-emergent adverse event; TIS, tislelizumab Data cut-off: August 10, 2020 Citation Format: Jie Wang, Zhiyong Ma, Dingzhi Huang, Yun Fan, Xinmin Yu, Sheng Hu, Ziping Wang, Zhihua Liu, Devrim Cabuk, Mahmut Gumus, Yiyuan Ma, Yan Wang, Yan Ma, Caicun Zhou. Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced squamous (sq) non-small-cell lung cancer (NSCLC): Sub-analysis from phase 3 RATIONALE-303 randomized clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT554.

Abstract Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutation has been reported in about 25% of patients with acute myeloid leukemia (AML). In contrast to patients with FLT3-ITD wild-type, AML with FLT3-ITD mutations have an inferior survival, primarily due to shorter remission duration and higher relapse rate. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the survival for FLT3-ITD AML, the rate of leukemia relapse remains high. Patients experiencing leukemia relapse post-transplants have a dismal prognosis. Recent studies have demonstrated that sorafenib monotherapy or in combination with other therapeutic strategies could induce sustained responses for patients with FLT3-ITD relapsed post-transplants. The aim of this study is to evaluate the efficacy of sorafenib combined with other therapeutic strategies for AML with FLT3-ITD relapsed after allo-HSCT. MethodsA total of 76 AML with FLT3-ITD relapsed after allo-HSCT from January 2012 to May 2017 were enrolled in this study. Depending on whether receiving salvage therapy containing sorafenib, patients were divided into 2 groups: sorafenib group (n=49) and non-sorafenib group (n=27). On the basis of the differences of therapeutic regimens, patients were divided into 4 subgroups, including sorafenib+ chemotherapy+donor lymphocyte infusion (DLI) (Group A, n=39), sorafenib+ chemotherapy (Group B, n=10), chemotherapy +DLI (Group C, n=15), and monochemotherapy (Group D, n=12). Outcomes of different therapeutic regimens were compared. Results Forty patients obtained complete remission (CR) and 12 partial remission after salvage therapies, with the CR and overall response (OR) rates of 52.6% and 68.4%. The CR and OR rates were 65.3% and 81.6% in the sorafenib group, compared with 29.6% and 44.4% in the non-sorafenib group (P=0.003, P=0.001). Subgroup analysis showed that the CR and OR rates in Group A were higher than that in Group D (P=0.006, P=0.001), and they were similar to that in Groups B and C (all P values >0.008). There were also no significant differences in the CR and OR rates among Groups B, C, and D (all P values >0.008). With a median follow-up of 245 (range 30-1992) days after relapse, 26 patients remained alive and 50 died. The 3-year overall survival (OS) was 33.8% (95% CI, 23.3%-44.5%). The 3-year OS in the sorafenib group was superior to that in the non-sorafenib group (42.0% vs 18.5%, P=0.002). Subgroup analysis revealed that sorafenib combined with chemotherapy followed by DLI was superior to other regimens, with 3-year OS of 47.8%, 20.0%, 20.0%, and 16.7% in Groups A, B, C, and D, respectively (P=0.007). The incidences of acute and chronic GVHD as well as the mortality of GVHD after salvage therapies were similar among the four groups (P=0.304, P=0.429, P=0.601, respectively). Multivariate analysis revealed that salvage therapy containing sorafenib was the only protective factor for OS (P=0.022, hazard ratios= 0.479). ConclusionsSalvage therapy containing sorafenib was superior to that not containing sorafenib, and sorafenib combined with chemotherapy followed by DLI revealed optimal efficacy for relapse of AML with FLT3-ITD after allo-HSCT. Disclosures Fan: National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

Abstract Background: At a predefined interim analysis (IA), RATIONALE-303 (NCT03358875) demonstrated improved overall survival (OS) for TIS vs D in the intent-to-treat (ITT), with a manageable safety profile. Disease characteristics, standard of care and treatment/prognosis differ between histologic types of NSCLC. Here, we report on the non-sq population. Methods: 805 patients with histologically confirmed, advanced NSCLC with progressive disease during or after ≥ 1 platinum (Pt)-containing chemotherapy regimen were randomized (2:1) to TIS 200 mg or D 75 mg/m2 every 3 weeks until disease progression, intolerable toxicity, or withdrawal. Histology (sq vs non-sq) was a randomization stratification factor. Dual primary endpoints were OS in the ITT and PD-L1 ≥ 25% populations. A prespecified IA was conducted after ~426 deaths (76% of planned events). Efficacy and safety were assessed in 435 randomized patients with non-sq histology. Results: Baseline characteristics of non-sq patients were balanced between treatment arms and similar to the ITT population. As of August 10, 2020, at median follow-up of 20 and 17 months (mo), respectively, median (95% CI) OS was longer with TIS (18.6 mo [15.41, 23.16]) vs D (13.8 mo [9.43, 17.94]) in the non-sq ITT population, and objective response rate (ORR) and duration of response (DoR) were also improved for TIS vs D (Table). 95.5% (TIS) and 97.9% (D) of patients had ≥ 1 treatment-emergent adverse event (TEAE) and 39.0% (TIS) and 70.9% (D) of patients had ≥ Grade 3 TEAEs. The most common TEAEs were anemia, aspartate aminotransferase increased and alanine aminotransferase increased (TIS arm), and alopecia, anemia and neutrophil count decreased (D arm). Conclusions: TIS prolonged OS, consistent with the overall ITT population, with a favorable safety profile in patients with advanced non-sq NSCLC who progressed after a Pt-containing regimen. Table Efficacy* TIS (n=287) D (n=148) Median OS, mo (95% CI) 18.6 (15.41, 23.16) 13.8 (9.43, 17.94) OS HR (95% CI)† 0.71 (0.538, 0.929) P=0.0064‡,§ Median PFS, mo (95% CI) 2.5 (2.14, 4.01) 3.6 (2.17, 4.14) PFS HR (95% CI)† 0.84 (0.660, 1.062) P=0.0686‡,§ ORR, n (%) 60 (20.9) 14 (9.5) Median DoR, mo (95% CI) 11.7 (6.80, 14.65) 6.2 (2.10, 7.16) Safety** TIS (n=287) D (n=141) TEAEs ≥ 15% of patients in either arm, n (%) All grades ≥ Grade 3 All grades ≥ Grade 3 Anemia 76 (26.5) 11 (3.8) 56 (39.7) 6 (4.3) AST increased 64 (22.3) 5 (1.7) 18 (12.8) 0 (0.0) ALT increased 63 (22.0) 4 (1.4) 24 (17.0) 0 (0.0) Cough 59 (20.6) 4 (1.4) 25 (17.7) 0 (0.0) Weight decreased 44 (15.3) 2 (0.7) 13 (9.2) 0 (0.0) Decreased appetite 41 (14.3) 3 (1.0) 26 (18.4) 0 (0.0) Hypoalbuminemia 37 (12.9) 0 (0.0) 23 (16.3) 0 (0.0) Nausea 37 (12.9) 0 (0.0) 22 (15.6) 0 (0.0) Constipation 31 (10.8) 0 (0.0) 22 (15.6) 0 (0.0) Asthenia 29 (10.1) 1 (0.3) 29 (20.6) 8 (5.7) Neutrophil count decreased 8 (2.8) 1 (0.3) 53 (37.6) 36 (25.5) White blood cell count decreased 8 (2.8) 0 (0.0) 42 (29.8) 26 (18.4) Neutropenia 7 (2.4) 3 (1.0) 44 (31.2) 38 (27.0) Leukopenia 6 (2.1) 0 (0.0) 38 (27.0) 22 (15.6) Alopecia 0 (0.0) 0 (0.0) 70 (49.6) 2 (1.4) *Efficacy analysis set - non-sq patients; †Stratified; ‡One-sided stratified log-rank test; §Descriptive P-value; **Safety analysis set - non-squamous patients ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI; confidence interval; DoR, duration of response; HR, hazard ratio; mo, months; NE, not evaluable; ORR, objective response rate; PFS, progression-free survival; TEAE, treatment-emergent adverse event Data cut-off: August 10, 2020 Citation Format: Ying Cheng, Dingzhi Huang, Zhiyong Ma, Yun Fan, Jie Wang, Xinmin Yu, Mikhail Dvorkin, Gareth Rivalland, Yiyuan Ma, Yan Wang, Yan Ma, Caicun Zhou. Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced non-squamous (non-sq) non-small-cell lung cancer (NSCLC): Subanalysis from the RATIONALE-303 phase 3 randomized clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT553.

BackgroundThe impact of immunosuppressants on COVID-19 vaccination response and durability in patients with immune-mediated inflammatory diseases (IMID) is yet to be fully characterized. Humoral response may be attenuated in these patients especially those on B cell depleting therapy and higher doses of corticosteroids, but data regarding other immunosuppressants are scarce.ObjectivesWe aimed to investigate antibody and T cell responses and durability to SARS-CoV-2 mRNA vaccines (BNT162b and/or mRNA 1273) in IMID patients on immunomodulatory maintenance therapy other than B-cell depleting therapy and corticosteroids.MethodsThis prospective observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with IMIDs (psoriatic arthritis, psoriasis, inflammatory bowel disease and rheumatoid arthritis) with or without maintenance immunosuppressive therapies (anti-TNF, methotrexate/azathioprine [MTX/AZA], anti-TNF + MTX/AZA, anti IL12/23, anti-IL-17, anti-IL23) compared to healthy controls. Automated ELISA for IgGs to spike trimer, spike receptor binding domain (RBD) and the nucleocapsid (NP) and T-cell release of 9 cytokines (IFNg, IL2, IL4, IL17A, TNF) and cytotoxic molecules (sFasL, GzmA, GzmB, Perforinin) in cell culture supernatants following stimulation with spike or NP peptide arrays were conducted at 4 time points: T1=pre vaccination, T2=median 26 days after dose 1, T3=median 16 days after dose 2 and T4=median 106 days after dose 2. Neutralization assays against four SARS-CoV-2 variants (wild type, delta, beta and gamma) were conducted at T3.ResultsWe followed 150 subjects: 26 healthy controls and 124 IMID patients: 9 untreated, 44 on anti-TNF, 16 on anti-TNF with MTX/AZA, 10 on anti-IL23, 28 on anti-IL12/23, 9 on anti-IL17, 8 on MTX/AZA (Table 1). Most patients mounted antibody and T cell responses with increases from dose 1 to dose 2 (100% seroconversion at T3) and some decline by T4, with variability within groups. Antibody levels and neutralization efficacy was lower in anti-TNFgroups (anti-TNF, anti-TNF + MTX/AZA) compared to controls and waned by T4 (Figure 1). T cell responses were not consistently different between groups. Pooled data showed a higher antibody response to mRNA-1273 compared to BNT162b.Table 1.Baseline characteristics of study participantsControluntreated IMIDAnti- TNFAnti- TNF +MTX/AZAAnti-IL-23Anti -IL-12/23Anti -IL-17MTX/AZAn=26n=9n=44n=16n=10n=28n=9n=8p-valueIMID*N/A IBD9301002704 Psoriasis1318122 PA0732172 AS0830010 RA1100011Age median years [IQR]36 [26-46]33 [27-41]38 [30-51]53 [44-59]48 [45-61]34 [28-47]49 [46-61]42 [31-55]<0.001^Sex male (%)16 (62)5 (56)18 (41)8 (50)5 (50)13 (46)6 (67)4 (50)0.772~BMImedian kg/m2 [IQR]25 [23-28]26 [22-27]22 [24-26]26 [24-28]27 [24-35]22 [21-24]32 [26-34]26[25-33]0.001^Vaccine interval median days [IQR]74 [35-84]54 [31-64]60 [45-69]64 [50-72]74 [35-84]62 [49-69]65 [52-75]58 [21-97]0.372^*multiple IMIDs per patient possibleFigure 1.Antibody responses (A) Anti spike and anti RBD IgG levels at indicated time points. Blue line represents median ratio in convalescent patients. The red line is the seropositivity threshold: the median antibody level of those that pass both a 1% false positive rate and show ≥3SD from the log means of the negative controls. (B) Relative ratio of RBD, spike and NP across time. Black and gray lines indicate median and mean values, respectively. *p≤0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001ConclusionFollowing 2 doses of mRNA vaccination there is 100% seroconversion in IMID patients on maintenance therapy. Antibody levels and neutralization efficacy in anti-TNF group are lower than controls, and wane substantially by 3 months after dose 2. These findings highlight the need for third dose in patients undergoing treatment with anti-TNF therapy and continued monitoring of immunity in these patient groups, taking into consideration newer variants and additional vaccine doses.AcknowledgementsThis work was funded by a donation from Juan and Stefania Speck and by grants VR-1 172711, VS1-175545, FDN-143250, GA1- 177703 and GA2- 177716, from Canadian Institutes of Health Research and COVID Immunity task force and by Sinai Health FoundationDisclosure of InterestsNaomi Finkelstein: None declared, Roya M. Dayam: None declared, Jaclyn Law: None declared, Rogier Goetgebuer: None declared, Gary Chao: None declared, Kento T. Abe: None declared, Mitchell Sutton: None declared, Joanne M. Stempak: None declared, Daniel Pereira: None declared, David Croitoru: None declared, Lily Acheampong: None declared, Saima Rizwan: None declared, Klaudia Rymaszewski: None declared, Raquel Milgrom: None declared, Darshini Ganatra: None declared, Nathalia V. Batista: None declared, Melanie Girard: None declared, Irene Lau: None declared, Ryan Law: None declared, Michelle Cheung: None declared, Bhavisha Rathod: None declared, Julia Kitaygorodsky: None declared, Reuben Samson: None declared, Queenie Hu: None declared, Nigil Haroon: None declared, Robert Inman Consultant of: AbbVie, Janssen, Lilly, Novartis., Grant/research support from: AbbVie, Novartis, Vincent Piguet Consultant of: AbbVie, Almirall, Celgene, Janssen, Kyowa Kirin Co. Ltd, LEO Pharma,Novartis, Pfizer, Sanofi, UCB, and Union Therapeutic, Grant/research support from: Unrestricted educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Lilly, L’Oréal, NAOS, Novartis, Pfizer, Pierre-Fabre, Sandoz, and Sanofi, Mark Silverberg Speakers bureau: AbbVie, Janssen, Takeda, Pfizer, Gilead and Amgen, Consultant of: AbbVie, Janssen, Takeda, Pfizer, Gilead and Amgen, Grant/research support from: AbbVie, Janssen, Takeda, Pfizer, Gilead and Amgen, Anne-Claude Grigras: None declared, Tania H. Watts: None declared, Vinod Chandran Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, Eli-Lilly.

Nitrogen is a paramount important essential element for all living organisms. It has been found to bea crucial structural component of proteins, nucleic acids, enzymes and other cellular constituents which are inevitable for all forms of life. In the atmosphere, the percentage of nitrogen is very high (N2, 78%) compared to other inorganic gases. However, most organisms have practically no direct access to this nitrogen. While plants can not directly uptake nitrogen from atmosphere, they are capable of assimilating other forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-). For agricultural crop production, artificial fixation of nitrogen is heavily utilized and it is an expensive process that requires high temperatures (at least 400 °C) and pressures (around 200 atm). It has been conspicuously demonstrated that indiscriminate use of fertilizer hampers soil physical, chemical and micro biological properties and also a potential risk to environment e.g. water quality. Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching. Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, only 1-2% of the nitrogen fixation in the world occurs through the natural process of lightening. Notably, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae. Against the backdrop, we are accentuated on an environmentally friendlyand themost sustainable approach to increase productivity for legume and non-legume crops. Till today, the term biological nitrogen fixation (BNF) has received much attention as a sustainable alternative; this process facilitates atmospheric nitrogen to convert into ammonia by rhizobia in specialized plan organs termed “root nodules”. This review article seeks to better understand plant mechanisms involved in the development of root nodules in soybean. Soybean (Glycine max) is one of the most important oil crops and a source of animal feed protein in the world. It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Oldroyd, Murray et al. 2011). Biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. A better understanding of how nodules form and function is important for selection or generation of soybean genotypes with better nitrogen fixation capacity. Soybean nodules originate from root cortex via de novo cell differentiation (Oldroyd 2013). Consequently, two major nodule development zones are formed for instance; the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. It is not clear what early signaling pathways driving the conspicuous development of the nodule zones. My research is aimed at filling this knowledge gap by illustrating the molecular signatures that paves the way to cellular differentiation in root nodule development in soybean. Based on initial evidence obtained by the Subramanian lab, we hypothesize that microRNAs (miRNAs) play important regulatory roles in spatio-temporal expression of their target genes during nodule developmental in soybean. For instance, the regulation of auxin sensitivity by miR160 has been found to be crucial for formation of nodule primordia and vasculature in the parenchyma (Marie Turner 2013). Against this backdrop, this review article focused on nuclear and cytoplasmic transcriptome as well as miRNA profiles of parenchyma and primordial tissues and determine the relative abundance and differentially expressed mRNAs and regulatory role of miRNAs in cell differentiation and nodule development. Root nodule a sustainable alternative to fix atmospheric nitrogen Atmospheric nitrogen percentage is very high (N2, 78%) compared to other inorganic gases (Mary Elvira 1932). However, most of the organisms have practically no direct access to this nitrogen. Nevertheless, plants can not directly uptake nitrogen from atmosphere but they are capable of assimilating only very specific forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-) (Bytnerowicz and Fenn 1996, Peter M. Vitousek 1997) (Sponseller, Gundale et al. 2016). Virtually, nitrogen has been found to be a crucial structural component of proteins, nucleic acids, enzymes, and other cellular constituents which are inevitable for all forms of life (O'Brien, Vega et al. 2016). For agricultural crop production, artificial fixation of nitrogen is heavily utilized. It is an expensive process that requires high temperatures (approx. 400 °C) and pressures (approx. 200 atm) (Witschi 2000). It has been conspicuously demonstrated that indiscriminate use of N fertilizer hampers the diversity of the bacterial community and decreases soil C and N concentrations (Verzeaux, Alahmad et al. 2016). Notably, it has been demonstrated as a potential risk to environment e.g. water quality (Zhao, Sha et al. 2016) (Sponseller, Gundale et al. 2016). Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching (Johnson 1996, Peter M. Vitousek 1997). Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, over 90 % of the nitrogen fixation in the world occurs through the natural process of lightening and microorganisms. Furthermore, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae (Cheng 2008). It has been demonstrated that Bradyrhizobium strains substantially escalated soybean grain yield, and protein content up to 57% and 26%, respectively (Zimmer, Messmer et al. 2016). Against the backdrop, we are accentuated on an environmentally friendly and a sustainable approach to increase the productivity for legume and non-legume crops. Literature mining depicted that biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. Rhizobia infection leads to the root nodule development In the natural environment, plants are continuously confronted with pathogenic and symbiotic microbes. Symbioses involves mutual exchange of diffusible signal molecules, first endophytic bacteria (rhizobia) are attracted by the plant root exudates flavonoids which are perceived and triggered the bacterial nodulation (nod) genes. Consequently, the bacteria synthesize specific lipochito-oligosaccharides, called nodulation (Nod) factors. This signal is perceived by the LysM receptor like kinase of host plant, it induces the root hair curling, and bacteria get access into the host epidermis through infection threads (ITs) and initiate cell division within the root cortex, leading to the progression of the root nodule meristem. In later stages of the interaction, bacteria are released from the infection threads into the plant cells, surrounded by membrane of plant origin. These bacteria multiply within the host cells and differentiate into the nitrogen fixing bacteroids (Udvardi and Day 1997) (Oldroyd 2013). Till now, integration of genetic and genomic approaches has revealed twenty-six genes to be involved in nodule development of Medicago truncatualaand Lotus japonicum (Kouchi, Imaizumi-Anraku et al. 2010). In addition, deep sequencing of the Medicago truncatularoot transcriptome has uncovered thousands of genes to be induced during Nod factor signaling and its resulting ethylene (ET) biosynthesis throughout the multiple development stages of indeterminate nodule (Larrainzar, Riely et al. 2015). Albeit the molecular mechanism of such regulation is not well understood. There has been a large-scale transcriptome analysis of B. japonicum-inoculated and mock-inoculated soybean root hairs. It has showed that a total of 1,973 soybean genes differentially expressed during root hair infection, particularly NFR5 and NIN genes (Libault, Farmer et al. 2010). Nevertheless, the signaling mechanisms directing the cellular differentiation of nodule are not known. Soybean root nodule organogenesis Soybean (Glycine max) has a genome size of 1.1 to1.5 Gb, it is partially diploidized tetraploid. It is one of the most important oil crops and a source of animal feed protein in the world (soybase.org/sb_about.php). It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Udvardi and Day 1997) (Oldroyd, Murray et al. 2011). Notwithstanding of the economic and environmental importance, there has been very few studies about quantitative trait loci (QTL) that controlling BNF traits, for instance nodule number, ration of nodule dry weight with nodule number, and shoot dry weight (SDW). It has been reported via composite interval mapping that approximately six QTLs bears very small effect on BNF traits (Santos, Geraldi et al. 2013). Besides, it has been demonstrated in earlier studies that nodules originate from root cortex via de novo cell differentiation into two different cell types, parenchymal and primordium (Celine Charon 1997) (Oldroyd&Downie 2008; Oldroyd 2013). In addition, early nodulin genes in legume for instance; Enod 40 gene reported to be expressed in root pericycle during the rhizobia infection and later it occupied in the dividing cortical cells (H. Kouchi and S. Hata 1993). Among the two major nodule development zones, the nodule primordium (Npr) in the middle which is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. Lately, a β- expansin gene, GmEXPB2 fused with GUS reporter gene which was observed to be preferentially expressed in nodule vascular trace and nodule vascular bundles. It indicated that GmEXPB2 might be crucial for nodule organogenesis. Over expression of GmEXPB2 contrast to suppressed GmEXPB2 transgenic lines found to be escalated nodule number, nodule mass and nitrogenase activity. It further suggested that GmEXPB2 might have influenced over root architecture, nodule formation and development, and profoundly yielding to biological N2 fixation (Li, Zhao et al. 2015). Even though, it is not clear what early signaling pathways driving the conspicuous development of the nodule zones. Against the back drop, to understand the regulation of auxin sensitivity by miR160 which is believed to be crucial for the formation of nodule primordia (Marie Turner 2013). Figure 1 a. Illustrating the progression of root nodule development through Rhizobial bacterial infection in the plant root leading to the determinate nodule (Oldroyd 2013). b. Nodule development zones A. Nodule primordial zone (Enod 40 gene) in the middle B. surrounding parenchyma (Enod 2 gene), differentiated from cortex (collected from Sen Subramanian lab). Regulatory small RNAs biogenesis and its molecular functions Regulatory small RNAs are ranged between 20 to 24 nucleotides which are ubiquitous elements of endogenous plant transcriptomics, a common response to exogenous viral infections and introduced double-stranded RNA (Axtell 2013). Three core enzymes families, for instance; RNAdependent RNA polymerase (RDR), Dicer like (DCL), and Argonaute (AGO) proteins paves the way of small RNA biogenesis and function in plants. Firstly, ribonuclease type III or DICERLIKE1 involves in the yield of a fold-back precursor RNA or primary miRNA (primiRNA) transcripts using an RNA templates in the nuclei. Later, the resulting miRNA-miRNA duplex which is originated in nucleus then translocated into cytoplasm. The guided miRNAmolecule is incorporated into ARGONAUTE (AGO) to form an active RISC complex to specific target RNAs that are complementary to the miRNA, and this process eventually follows up mRNA cleavage, represses the translation of the mRNAs or Chromatin modification. This phenomenon accentuated as an inhibition or silencing of the gene expression, which play a crucial role in the developmental process in plant and animal (Chapman and Carrington 2007) (Axtell 2013). Fig. 2 Regulation of gene expression events via RISC complex (modified from https://www.google.com/?gws_rd=ssl#q=mirna+picture+in+plants accessed on 7th February, 2016) Fig. 3 Gene expression events occurring in typical plant cell (modified https://www.google.com/search?q=transcription+and+translation accessed on 7th February, 2016) It has been found in several studies that most plant miRNAs are non-coding RNA, and small 21-24 nucleotide long (Cuperus, Fahlgren et al. 2011). It requires DCL1-clade DCL for their biogenesis and AGO1-clade AGO for their function (Wu, Zhou et al. 2010, Manavella, Koenig et al. 2012). In rice (Oryza sativa), DCL3 has been reported in the biogenesis of 24nt long miRNA that incorporated in AGO4 to regulate the target gene expression primarily through mRNA cleavage (Wu, Zhou et al. 2010). Argonaute proteins (AGO) form RNA inducing silencing complexes (RISC) with small RNAswhich is known as post-transcriptional gene silencing. It has typically four domains, for instance:N-terminal, PAZ, MID and PIWI domains. The MID-PIWI lobes are belongs to the C-terminus. It has been studied that MID-domains contains the specificity loop to recognize and bind to the 5’-phosphate of smRNAs. The PIWI domains contained the catalytic active site D-E-D-H/D. PAZ domain anchored the 2-nt overhang at the 3’ end of miRNAs. The N-terminal domain involved in the separation of miRNA-miRNA duplex and the slicer activity of the mRNA (Song, Smith et al.2004). There has been an expansion and duplications of AGO family members during plantevolution (Singh, Gase et al. 2015). The functional diversification of AGOs is indicating sRNAdirected regulatory pathways. The binding preference of AGO and sRNA is mainly assigned by the sequence of sRNA. In Arabidopsis, 10 AGO have been extensively studied (Liu et al. 2014). It has been demonstrated that AtAGO10 like AtAGO1, it recognized distinct structural features in miR165/miR166 duplex than involved by AtGO1. AtAGO10 found to regulate shoot apical meristem by decoying miR165/miR166 and subsequent repression of homeodomain-leucinezipper (HD-ZIP) gene expression (Zhu, Hu et al. 2011). Notably, 22 AGO proteins have been reported in Soybean (Glycine max). It has been found that genome duplication in Soybean resulted such a proliferation of AGOs. For example: its genome encodes two copies of AGO1, AGO2, AGO5, AGO4/9, AGO6 and AGO7 (Xiang Liu 2014). However, the molecular function of the plant AGO genes yet not very clear. There are several miRNA families that are conserved across the vast evolutionary distances from flowering plants to mosses (Cuperus, Fahlgren et al. 2011). It has been observed in another study that miRNA, and its target pairing found to be stable for a prolonged periods of plant evolution. On the flip side, another group demonstrated that conserved plant miRNAs and their targets are to somehow flexible. For instance; miR159 is a highly conserved miRNA that targets not only a subset of MYB mRNAs but also observed to target a non MYB mRNA, SGN-U567133 (Buxdorf, Hendelman et al. 2010). A mutant tomato transgenic line (miR159-resistant line) showed higher level of the SGN-U567133 transcript and exhibited defects in leaf and flower development. This result suggests that miR159 involves in a post-transcriptional regulation. Additionally, it is found to be crucial for the normal tomato development. Recently, the identification of miRNAs in the regulation of photoperiodic pathways in soybean have been reported through high throughput sequencing and qRT-PCR. Six libraries were constructed using Illumina Solexa, for instance; 0, 8, and 16 h under short day treatment, similar time points considered for the long the long day treatment. A total of 163 miRNAs families were reported which covered 318 plant miRNAs, and unclassified 81 novel predicted miRNAs. As expected, significant differences in abundance between short day and long day treatment was observed (Wenbin Li 2015). These findings provided evidence of miRNA in the regulation of flowering time that ultimately affects the seed yield and quality of soybean. The complex regulatory network of miRNA-mRNA interactions during viral infection has been revealed via small RNA seq (sRNA), degradome seq, and genome-wide transcriptome analysis. There has been a total of 253 soybean miRNAs found to be two-folds abundance compared with mock-inoculated control demonstrated through sRNA seq analysis. Among them 105 miRNAs were identified as potential targets of 125 transcripts that has been validated by degradome seq analyses. In addition, 2679 genes were detected via genome wide transcriptomic analysis. These genes have been differentially expressed during infection of soybean mosaic virus and among them 71 genes projected to induce in defense response (Hui Chen 2016). These findings suggested the regulatory role miRNA that governed the target gene expression during viral infection. Furthermore, the regulatory role of microRNAs (miRNAs) during Soybean- Bradyrhizobium japonicum mutualistic association was studied first by Subramanian et al. 2008. They sequenced approximately 350000 small RNAs of soybean root sample which were inoculated with B. japonicum. It helps to detect 20 conserved miRNAs loci based on the similarity to miRNAs in another plant species. In addition, 35 novel miRNAs were identified based on potential hairpin forming precursors in Soybean EST as well as shotgun genomic sequences (Subramanian, Fu et al. 2008). These findings advocated the potential role of miRNAs in the regulation of legumerhizobiumsymbiosis. In another study, 120 hairpin-forming precursor genes have been identified in soybean by Turner et al. In addition, they reported three novel miRNAs for instance; miR160, miR164 and miR393 found to be involved in auxin signaling (Turner, Yu et al. 2012). Moreover, the plant hormone auxin is thought to have a pivotal role in nodule organogenesis in determinate and indeterminate type of nodule. It indicates a redundancy and diversity of miRNAs family members that governs the formation of root nodule. It has been illustrated that auxin receptor gene family hushed by over expressed microRNA393. These plant roots found to be hypersensitive to auxin and yielded normal nodule. This observation advocated that only minimal/reduced auxin signaling is required for determinate nodule development. Likewise, overexpressed microRNA160 hushed a set of repressor auxin response transcription factor. These plant roots were hypersensitive to auxin and observed not to be reluctant in epidermal responses to rhizobia. Notably, it yielded to lower sized nodule primordium (Marie Turner 2013). This observation indicated that auxin hypersensitivity inhibits nodule organogenesis Organ specific expression of profile of miRNA and the potential targets were also studied. Two genes (Glyma10g10240 and Glyma17g05920) which were the target of miR169 but detected to be highly expressed in soybean nodule. Likewise, three potential targets of gma-new-miR13587 demonstrated to be highly expressed in the nodules than in the roots. As expected, gma-newmiR13587 found to be poorly expressed in the nodules than in the roots (Turner, Yu et al. 2012). There was an inverse expression pattern observed in between roots and nodules. Li et al., studied the transgene expression of three novel miRNAs namely, miR482, miR1512, and miR1515 in Soybean. They noticed a significant increase of nodule numbers while root length and later root density were normal in all tested miRNA lines. As expected, there were differential expression of these miRNAs in supernodulating and nonnodulating soybean mutants. They reported that 6 novel miRNAs decoyed 22 predicted target genes. And it was estimated via real time polymerase chain reaction and qRT-PCR (Li, Deng et al. 2010). It advocates that miRNAs have the signatory roles in soybean nodule development. Sequencing of small RNAs and Parallel analysis of RNA ends (PARE) libraries revealed to identify 284 nodule miRNAs, more than 500 target genes, and including 178 novel soybean miRNAs. It has been reported that ENOD93 only found to be expressed in nodule tissue not in other plant parts of Soybean. Ectopic expression of miR393j-3p and RNAi silencing approach to ENOD93 expression showed a significant reduction in nodule formation (Zhe Yan 2015). Therefore, this study showed a list of miRNAs and their potential target of nodulation genes. In the model legume (Medicago truncatula), 25 conserved miRNA families and 100 novel miRNA reads were detected by high-throughput sequencing. The expression of MtHAP2-1 (encodes a CCAAT binding transcription factor) to meristematic zones was restricted by miR169a which is found to be critical for the development of indeterminate type of nodule (Combier, Frugier et al. 2006). In another study, HDZIPIII transcripts were inhibited by overexpression of miR166, it dropped the number of symbiotic nodule and lateral root (Boualem, Laporte et al. 2008). To get insights into key genes of nodule zones, transcript profiles of specific cells/tissues were investigated at different time points from indeterminate nodules of M. truncatulausing laser capture micro dissection. It has been demonstrated from the comprehensive gene expression map that selected genes enriched in different cell/tissue types (Limpens, Moling et al. 2013). These findings indicated that organ specific gene expression could be controlled by the presence or absence of miRNAs. Recently, Agrobacterium rhizogenesmediated hairy root transformation has been applied as tool for exploring cell type specific gene expression in tomato. Cell type or tissue specific promoter introduced into INTACT and TRAP constructs via gateway cloning technology to develop binary vectors. INTACT method used to capture biotin tagged nuceli from specific cell types and TRAP method used for profiling of mRNAs or foot printing of individual ribosomes (Ron 2014). TRAP methodology is not required tissue fixation or single cell suspension. It has been successfully used to date in organisms ranging from D. melanogaster to mice and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts (Heiman, Kulicke et al. 2014). In this study, we would perform polysome isolation deploying gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18. Over the last one decade, there has been several microarrays-based studies which characterized transcriptional variations deployed in nodule formation. It has been embedded with couple of shortcomings, for instance; relative late time points study, incomplete representation of plant genes,discrimination of close paralogs, and reduced sensitivity. Lately, next generation sequencingtechnology have widened the horizon of transcription analyses in different legume species to detectsymbiosis induced changes in late nodule developmental stages. Against this backdrop, we areaccentuated to reveal early transcriptional changes induced in determinate type of soybean noduleby Bradyrhizobium japonicum. In determinate type of nodule, two major nodule development zones are formed for instance, the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr converted to N-fixation zone and the Npa contained vascular bundles. Of these facts, it is not clear what early signaling pathways driving the conspicuous development of thenodule zones. In this context, mechanisms regulate the distinct gene expression profiles in Npr andNpa cell types has not understood clearly. The proposed research study is aimed at filling this knowledge gap byillustrating the molecular signatures that paves the way to cellular differentiation in root noduledevelopment in soybean considering four different time points (5 dai, 7 dai, 10 dai& 14 dai). The hypothesisis microRNAs(miRNAs) play important regulatory roles in spatio-temporal expression of their target genesduring nodule developmental in soybean. For example, a gradient of microRNA localizationbetween nodule primordium and parenchyma cells could result in distinct differentiation of thesecell types. To test this hypothesis, one has to obtain both cell type-specific miRNA andtranscriptome (miRNA target) profiles. Since, the majority of miRNA regulation occurs in thecytoplasm, we reasoned that comparison of nuclear and ribosomal transcriptome profiles wouldreveal genes whose expression is potentially regulated by post transcriptional mechanisms such asmiRNA cleavage. Combining this information with cell type-specific miRNA profiles, andto test the above hypothesis and identify key miRNA-target pairs important for nodule celldifferentiation. The use of translating ribosome affinity purification (TRAP) of nodule zonecells, namely from parenchyma and primordial tissues, to obtain cytoplasmic transcriptomes data. Techniques to determine cell type specific expression profiles: TRAP methods TRAP is termed translating ribosome affinity purification, combines cell-type-specific transgene expression with affinity purification of translating ribosomes. It supersedes the need for tissue fixation, and facilitates to study the cell type-specific mRNA profiles of any genetically defined cell type. It has been successfully used to date in organisms ranging from D. melanogaster to mice, and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts. In this study, the polysome isolation using gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18 RPL18(Heiman, Kulicke et al. 2014, Ron 2014). Relative abundance and differentially expressed mRNAs profile in two different tissue specific zones would help to understand the effect of regulatory role of miRNAs in cell differentiation and nodule development. References: Axtell, M. J. (2013). "Classification and comparison of small RNAs from plants." Annu Rev PlantBiol 64: 137-159. 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Introducción: La preeclampsia-eclampsia es un trastorno sistémico del embarazo prevalente caracterizado por hipertensión y proteinuria, un signo de disfunción renal. Se sabe relativamente poco sobre sus efectos a largo plazo en el riñón ya sea en términos de daño físico medido por albuminuria o proteinuria, desarrollo de hipertensión arterial crónica, deterioro funcional medido por la reducción de tasa de filtración glomerular o insuficiencia renal crónica (ERC). Métodos: En el presente estudio analítico y retrospectivo se tomaron los datos de las historias clínicas de pacientes con antecedente de preeclampsia- eclampsia atendidas en el servicio de ginecología y obstetricia del Hospital de Especialidades Carlos Andrade Marín diagnosticadas desde enero 2008 hasta diciembre 2018 (grupo expuestas), y embarazadas sanas durante el mismo período de tiempo (grupo no expuestas), una vez aleatorizadas se realiza el seguimiento para establecer la prevalencia de algún grado de enfermedad renal crónica en los grupos. Resultados: Se incluyeron 201 casos en el grupo de preeclampsia (GPE) y 201 al grupo control (GC). Edad de 29.5 ± 6.8 años en GPE y 31.4 ± 6.5 en GC, P=0.30. Etnia hispánica 191 (95.0%) en GPE y 196 (97.5%) en GC, P=0.90.Escolaridad superior en 93 (46.3%) en GPE y 94 (46.8%) en GC. ERC (Estadio 1-5) OR=3.725 (IC95% 1.935 – 8.381), P=0.0002. ERC (Estadio 5) OR=1.764 (0.75 – 239.5), P=0.077. Etnia mestiza OR= 3.911, (IC95% 2.21 – 10.91) P=0.0001. Desarrollo de Hipertensión arterial 2.041 (IC95% 1.038 – 6.317) P=0.0413. Desarrollo de proteinuria OR= 2.193 (IC95% 1.164 – 15.083) P=0.0283. Conclusiones: Las mujeres con antecedente de preeclampsia-eclampsia en cualquiera de sus embarazos presentaron mayor riesgo de desarrollar cualquier grado de ERC. Introdución De las diferentes patologías asociadas a embarazo, los trastornos hipertensivos son los más prevalentes siendo la preeclampsia la forma más común de ellos. La tasa de preeclampsia (PE) varía entre un 5% y un 10% en los países desarrollados, esta cifra podría verse incrementada hasta alcanzar un 18% en algunos países en vías de desarrollo [1]. Esta patología se presenta concomitantemente con alteraciones renales reversibles como la insuficiencia renal aguda cuya recuperación ocurre habitualmente dentro de las seis semanas posteriores al parto; sin embargo, se sabe relativamente poco sobre los efectos a largo plazo en el riñón ya sea en términos de daño físico medido por albuminuria o proteinuria, deterioro de la función medido por reducción en tasa de filtración glomerular (TFG) o insuficiencia renal en etapa terminal [2]. La causa más frecuente de injuria renal aguda en el embarazo es la asociada a la preeclampsia-eclampsia, pese a que en Latinoamérica existen escasos datos, reportes establecen que aproximadamente el 57% de las gestantes con IRA correspondían a aquellas que presentaron desórdenes hipertensivos como la preeclampsia, con una mortalidad materna de menos del 2% [3, 4]. El desarrollo de un episodio de IRA se asocia a un fuerte y significativo riesgo de desarrollo y progresión de enfermedad renal crónica termina (ERCT) e incluso a diálisis crónica [5]. Otra de las posibles implicaciones de la preeclampsia-eclampsia a nivel renal y a largo plazo es la de presentar daño crónico per se al antecedente de preeclampsia así; la ERC se define como el “daño renal por al menos tres meses, definido por anormalidades estructurales o funcionales del riñón con o sin descenso del filtrado glomerular” [6]. A pesar de la normalización después del parto de todas las alteraciones maternas desarrolladas por la preeclampsia, dichas alteraciones no han sido suficientemente estudiadas por el paradigma ampliamente extendido de que la “cura” de la preeclampsia-eclampsia es el parto, sin embargo, estudios muestran consistentemente que las mujeres antes preeclámpticas experimentan un riesgo aproximadamente doble de eventos cardiovasculares que ocurren principalmente en la quinta y sexta década de la vida [7]. Además, se ha visto que estas mujeres desarrollan hipertensión crónica de 6 a 8 años antes en comparación con las mujeres con antecedentes de embarazo normotenso, en lo que respecta a la función renal existe evidencia que podría aumentar el riesgo de desarrollar daño renal crónico [8], si embargo hay estudios no concluyentes como el estudio de “Mannist o et al” demostró una relación de riesgo (HR) para el desarrollo de ERC después de la hipertensión inducida por el embarazo de (HR 1.91) pero no después de la preeclampsia (HR 0.75) [4]: otro estudio demostró lo contrario en una corte retrospectiva de mujeres con antecedente de preeclampsia con un riesgo relativo (RR) de 4.7 para el desarrollo de ERCT después de la corrección para los factores de riesgo tradicionales. Este riesgo se ha visto que se podría triplicar cuando las mujeres tienen más de un embarazo con preeclampsia [9]. El objetivo del presente estudio fue determinar el riesgo de desarrollo de ERCT en un grupo de mujeres embarazadas con pre y eclampsia, comparadas con un grupo control con 11 años de seguimiento. Materiales y métodos Diseño del estudio El presente estudio es observacional, de casos y controles, de tipo retrospectivo. Escenario El estudio se realizó en el departamento de Estadística, Gineco-obstetricia y nefrología del Hospital de Especialidades “Carlos Andrade Marín”, del Instituto Ecuatoriano de Seguridad Social en Quito-Ecuador, durante el periodo de 1ro de enero del 2021 al 30 de septiembre del 2021. El período de análisis retrospectivo correspondió a 11 años: Desde el 1 de enero del 208 al 31 de diciembre del 2018. Participantes Se incluyeron mujeres con embarazo. En el grupo de casos se registraron pacientes con del diagnóstico de pre-eclampsia y eclampsia. En el grupo control se registraron mujeres embarazadas en el mismo período, sin patologías. Se excluyeron casos con antecedentes de enfermedad renal crónica y/o aguda, pacientes con antecedente de hipertensión crónica y/o pre gestacional, pacientes con antecedente de diabetes mellitus tipo 1 y 2, pacientes con antecedente de cardiopatía preexistente y pacientes con diagnóstico de cualquier enfermedad crónica que predisponga a desarrollo de enfermedad renal (como diabetes). Se eliminaron casos con datos incompletos para el análisis, con historias clínicas incompletas o sin seguimiento posterior al parto por al menos 1 año. Variables Las variables fueron: demográficas como edad, etnia, escolaridad, paridad. Variables clínicas: tasa de filtrado glomerular estimado por CKD-EPI, proteinuria, hematuria. Fuentes de datos/mediciones La fuente fue indirecta, se revisó el expediente electrónico institucional, el registro de los servicios de gineco-obstetricia. Los resultados de laboratorio fueron obtenidos del registro electrónico del laboratorio. El diagnóstico de preeclampsia se estableció con los criterios clínicos de: hipertensión presente >140/90 mmHg, proteinuria >300 mg/24 h, Trombocitopenia <150.000/u, alteración hepática con LDH > 600 UI/L, AST o ALT > 70 UI/L. Síntomas Vasomotores presentes: cefalea, epigastralgia, tinitus o escotomas. La eclampsia se estableció con Criterios clínicos de convulsiones en pacientes con preeclampsia. La enfermedad renal se clasificó en 5 estadios según la tasa de filtrado glomerular. La proteinuria se declarada positiva cuando la concentración fue mayor a 150 mg/24 horas o a la tirilla reactiva dio 1+. Sesgos Con el fin de evitar posibles sesgos de entrevistador, de información y de memoria, los datos fueron custodiados durante todo el tiempo por el investigador principal con una guía y registros aprobados en el protocolo de investigación. El sesgo de observación y selección fueron evitados con la aplicación de los criterios de selección de los participantes. Se consignaron todas las variables clínicas y paraclínicas del periodo ya comentado. Dos investigadores de manera independiente analizaron cada uno de los registros por duplicado y se consignaron las variables en la base de datos una vez verificada su concordancia. Tamaño del estudio La muestra fue probabilística, se usó la fórmula: n=2p*q(zα+zβ)2/(p1-p0)2, con un error alfa de 0.05, nivel de confianza del 95%, zα= 1.96, zβ= 0.842, p0 = 0.10, p1 = 0,2, el tamaño muestral fue de 200 casos y 200 controles. Variables cuantitativas Se utilizó estadística descriptiva. Se expresaron los resultados en escala en medias y desviación estándar. Los datos categóricos como el sexo se presentan en proporciones. Análisis estadístico Se utiliza estadística inferencial. Se utilizó la Prueba de Chi cuadrado para demostrar si existe relación entre las variables; para conocer el grado de asociación se usó el Riesgo Relativo (RR) con el intervalo de confianza del 95% y el valor P. El paquete estadístico utilizado fue SPSS 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Resultados Participantes Ingresaron al estudio 402 pacientes, 201 casos y 201 controles. Características basales de la población de estudio Las características de la población se presentan en la tabla 1. No hubo diferencias poblacionales con respecto a la edad, etnia, escolaridad o paridad al inicio del estudio. Desarrollo de enfermedad renal En las consultas de seguimiento se registró la presencia de enfermedad renal crónica en 35/201 casos (17.41%) versus 10/201 controles (4.98%) P<0.001. El tiempo transcurrido entre el diagnóstico de pre-eclampsia / eclampsia y el desarrollo de ERC fue de 3.95 años, el tiempo mínimo fue de 3.21 años y el máximo de 4.7 años (IC 95%). Se analizó el desarrollo de ERC en la etnia mestiza (hispánica) siendo un factor de riesgo (Tabla 2). Análisis secundarios Determinación mediante regresión logística de probabilidad de que ocurra ERC en función de variables con significancia estadística analizadas previamente en donde, se ratifica al antecedente de preeclampsia con un valor B de 1.27; P=0.001 (IC 95% 1.689 – 7.55) como factor predictor de ERC (Tabla 3). Discusión El antecedente de PE se ha estudiado como factor de riesgo para desarrollo de ERC, en este contexto los principales resultados en nuestro estudio fueron los siguientes: La incidencia de la preeclampsia se identifica entre 5 y 10%, cifras que pueden considerarse relativamente bajas, sin embargo, en algunos países constituye la primera causa de muerte materno-fetal y perinatal, no obstante estar identificada como una atención prioritaria [1, 10]. La asociación entre la preeclampsia y ERC es alta, así lo revela la razón de momios estimada no obstante exista esta asociación, no se puede afirmar que la preeclampsia es un factor de riesgo para ERC con el peso señalado por la imposibilidad de muchos estudios de controlar todas las variables que pudieran intervenir en el desarrollo a futuro de ERC [10 - 12]. Buscamos responder la interrogante sobre la relación de riesgo que existe entre el antecedente de preeclampsia y el desarrollo de ERC Esta asociación se ha investigado desde hace algunos años en pacientes con ERC y fuente de continuo trabajo [10, 13]. En estudios recientes el antecedente de PE ha sido asociado como factor de riesgo para el desarrollo de ERC [14], actualmente esta asociación es considerada objeto de observación para el seguimiento personalizado y determinación de factores de riesgo potencialmente controlables en el desarrollo de ERC. En el presente estudio la prevalencia de ERC atribuible a antecedente de preeclampsia fue de 17.41%, similar a los resultados obtenidos previamente [10 - 12]. El objetivo principal del estudio es demostrar la asociación entre el antecedente de PE y el desarrollo de ERC, además se incorporó una definición más amplia de ERC utilizando la proteinuria, hematuria y TFGe como determinantes de ERC, similar al estudio publicado previamente [15]. La existencia del antecedente de preeclampsia supone un riesgo relativo (RR) de 3.30 (IC 95%: 1.672 – 6.513), P< 0.05 para el desarrollo de ERC, valor muy parecido a los encontrados en un estudio previo con un RR 4.77 (IC 95%: 3.88 - 5.86) [15]. Estos resultados sugieren que debe prestarse atención al antecedente de preeclampsia para brindar un seguimiento nefrológico oportuno a esta población. El presente estudio describió que el tiempo promedio para presentar ERC en pacientes con preeclampsia fue de 3.95 años con un límite inferior de 3.21 años y uno superior de 4.7 años, estos datos difieren discretamente de los encontrados en Villarreal [6]. Con el objetivo de fortalecer el hallazgo de riesgo del antecedente de PE en el desarrollo de ERC se hizo el análisis de regresión logística multivariada, donde se incluyeron todas aquellas variables que resultaron tener significancia estadística encontrándose a la PE como único factor predictor de riesgo en el desarrollo de ERC con un valor B de 1.27; P=0.001 (IC 95% 1.689 – 7.55) como factor predictor de ERC, hallazgo que, ratifica el análisis estadístico previo. Conclusiones La preeclampsia es un factor asociado a ERC, conocimiento que puede ser utilizado para recordar al personal de salud la implicación de la preeclampsia en la salud de la mujer en edad fértil a corto y largo plazo, y la necesidad de implementar estrategias de prevención y control de ERC. La prevalencia de ERC en pacientes con antecedente de PE es del 17.41% valor comparable a la prevalencia en otros estudios. La población estudiada que desarrolló ERC corresponde a una población joven, al respecto la literatura identifica 40 años como edad promedio, grupo considerado como adulto joven, escenario que se puede considerar crítico por las repercusiones sociales si se asume que la mujer representa el 50% de la población mundial. El tiempo promedio para aparición de ERC entre el antecedente de PE y la aparición de cualquier forma de ERC fue de 3,95 años, con este estudio se sugiere que al menos un subconjunto de mujeres con datos previos de preeclampsia necesita seguimiento clínico para tamizaje de enfermedad renal en los años inmediatamente posteriores el embarazo. Abreviaturas ERC: enfermedad renal crónica. PE: pre-eclampsia. RR: riesgo relativo. OR: Odds ratio. Información suplementaria: Materiales suplementarios no han sido declarados. Agradecimientos: No aplica. Contribución de los autores: Norlys Margoth Fontalvo Díaz: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Boris Marcelo Torres Zavala: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Jorge Washing-ton Vélez Páez: Metodología, validación, supervisión, redacción: Revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Finaciamiento: Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales: Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar Este estudio fue aprobado por el comité de bioética (CEISH) del Hospital Carlos Andrade Marín. Consentimiento para publiación: No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés: Los autores reportan no tener conflictos de interés. 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Background: Circulating levels of the chemokine fractalkine (FKN) are increased in patients with chronic heart failure (HF) and our studies show that aged mice lacking the prostaglandin E2 EP4 receptor subtype (EP4 KO) have increased cardiac FKN coupled with a phenotype of dilated cardiomyopathy. However, whether FKN is a causal factor for HF is not well established. Hypothesis: FKN contributes to the pathogenesis of HF post myocardial infarction (MI) and EP4 KO mice have a better response to anti-FKN treatment due to elevated FKN levels. Methods: Male EP4 KO mice and wild type (WT) littermates underwent surgery to induce MI. Mice were treated with an anti-FKN antibody (40μg/kg/day, ip) or IgG immediately after MI and echocardiography was performed 2 wks post MI. Hearts were excised for infarct size determination, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) determined by morphometric analysis and macrophage infiltration using immunohistochemistry. Results: Anti-FKN treatment improved cardiac function and prevented remodeling (Table). In situ zymography revealed that gelatinase activity was markedly reduced by anti-FKN treatment in both strains. Moreover, anti-FKN treatment tended to improve survival in EP4 KO mice (p = 0.06, n=20). Conclusions: (1) FKN contributes to the pathogenesis of HF and anti-FKN treatment improves cardiac function and reduces cardiac remodeling. This may be related to reduced macrophage infiltration and decreased gelatinase activity.(2) Contrary to our hypothesis, EP4 KO mice do not have an enhanced response to anti-FKN treatment.

The D 1 R and AT 2 R are interdependent natriuretic receptors that are critical for the regulation of renal sodium balance and are implicated in both hypertension and salt-sensitivity. D 1 R and AT 2 R stimulation with the D 1 R agonist fenoldopam (FEN) and Angiotensin III (AngIII), selectively increases cAMP and cGMP, respectively, leading to D 1 R and AT 2 R recruitment to the cell surface (measured by fluorescent extracellular receptor epitope specific antibodies). The interdependence of the D 1 R and AT 2 R recruitment was investigated following AT 2 R stimulation with AngIII (10 nmol/L 1 hour) which leads to D 1 R cell surface recruitment using a normally D 1 R/Gs coupled cell line (i22) (VEH 8209±863, AngIII 19485±3425 RFU, n=6, p<0.05) but not in a D 1 R uncoupled from Gs cell line (i19). These data were verified by increasing intracellular sodium with monensin (100 μM, 1 hr) and measuring cell surface binding with a fluorescent labelled D 1 R agonist SKF83566 (10 nmol/L, 1 hr, i22 1.67±0.7 fold, n=5, p<0.0001, i19, NS). The importance of dopamine in regulating these receptor actions was shown by stimulating the AT 2 R with AngIII and measuring D 1 R recruitment followed by blockade of amino acid decarboxylase using either carbidopa or benzeraside (100 μM each, 1 hour). Additionally, FEN stimulated D 1 R surface recruitment is blocked by the AT 2 R inhibitor PD123319 (1 μM, 1 hour) and the coupling defect is fully rescued by 8Br-cGMP (1 mmol/L, 1 hour), a cell permeable second messenger normally thought to signal specifically through the AT 2 R. We then show that FEN stimulation leads to increased production of AngIII only in the D 1 R/Gs coupled i22 cell line (5.82±0.43 fold, n=6, p<0.05) but not in i19 the D 1 R/Gs uncoupled cell line and this production was blocked with an aminopeptidase A inhibitor, EC-33 (10 μmol/L, 1 hour). Addition of 8Br-cAMP (1mmol/L 1 hour) not only leads to an increase in AngIII production, but also cGMP production (4.33±0.36 fold, n=6, p<0.05) that is blocked by PD123319 (potent, selective, non-peptide angiotensin AT 2 R antagonist, 1 μM, 1 hour). In summary we not only show that dopaminergic stimulation leads to increased AngIII production in a D 1 R coupled manner, but also that AngIII stimulation of AT 2 R leads to dopaminergic activation in a D 1 R coupled manner.

AbstractWe present an analysis of fin whale (Balaenoptera physalus) songs on passive acoustic recordings from the Pelagos Sanctuary (Western Mediterranean Basin). The recordings were gathered between 2008 and 2018 using 2 different hydrophone stations. We show how 20 Hz fin whale pulses can be automatically detected using a low complexity convolutional neural network (CNN) despite data variability (different recording devices exposed to diverse noises). The pulses were further classified into the two categories described in past studies and inter pulse intervals (IPI) were measured. The results confirm previous observations on the local relationship between pulse type and IPI with substantially more data. Furthermore we show inter-annual shifts in IPI and an intra-annual trend in pulse center frequency. This study provides new elements of comparison for the understanding of long term fin whale song trends worldwide.

Abstract BACKGROUND AND AIMS Finerenone (FIN: an oral, nonsteroidal mineralocorticoid receptor antagonist) and canagliflozin (CAN: a sodium-glucose cotransporter 2 inhibitor) demonstrated cardiorenal efficacy in patients with chronic kidney disease and type 2 diabetes on top of renin–angiotensin system blockade in phase III placebo-controlled studies (FIDELIO-DKD [NCT02540993] for FIN; CREDENCE [NCT02065791] for CAN) [3,2]. In the absence of head-to-head studies, we assessed FIN and CAN in this patient population while appropriately accounting for meaningful differences between the trials. METHOD We performed an anchored matching-adjusted indirect comparison (MAIC), with placebo (PBO) as a common comparator, to generate measures of efficacy and safety while accounting for differences between the two study populations [3]. Individual patient-level data from FIDELIO-DKD and published data from CREDENCE were used [1,[2]. Weights were calculated and assigned to each patient in FIDELIO-DKD so the weighted population of FIDELIO-DKD matched that of CREDENCE for selected baseline characteristics, e.g. mean estimated glomerular filtration rate (eGFR; 44.3 and 56.2 mL/min/1.73 m2 in FIDELIO-DKD and CREDENCE, respectively). Weights were obtained from a logistic regression model of the odds of enrolment in CREDENCE and FIDELIO-DKD for baseline characteristics believed to be effect modifiers. Hazard ratios (HRs) with 95% confidence intervals (CIs) comparing FIN and PBO for time-to-event endpoints were estimated based on the weighted population of FIDELIO-DKD. HRs with 95% CIs comparing FIN and CAN were then calculated from results of the previous step and published data from CREDENCE [2]. This analysis evaluated the cardiorenal composite endpoint from CREDENCE (kidney failure [dialysis, transplantation or sustained eGFR &lt; 15 mL/min/1.73 m2), a doubling of serum creatinine level or death from kidney or cardiovascular disease) [2] and hyperkalaemia. A sensitivity analysis that matched patients based on their history of heart failure was performed. RESULTS Calculation of the weights for the FIDELIO-DKD population (N = 5674) resulted in an effective sample size of 1288 for the pseudo-population formed by the weighting to compare with the CREDENCE population (N = 4401). For the cardiorenal composite endpoint, the HR (95% CI) for FIN and PBO based on reweighted FIDELIO-DKD data was 0.72 (0.59–0.90) and the MAIC-based HR (95% CI) for FIN and CAN was 1.03 (0.79–1.35) (P = 0.802). For hyperkalaemia, the MAIC-based HR (95% CI) for FIN and CAN was 2.25 (1.67–3.03) (P &lt; 0.001). Similar efficacy and safety results were demonstrated in the sensitivity analysis. CONCLUSION The MAIC for FIDELIO-DKD and CREDENCE enabled more robust assessment of FIN and CAN when a similar patient population was considered. There was no evidence of a significant difference between FIN and CAN in the cardiorenal composite endpoint as assessed in CREDENCE. These results are consistent with a recent analysis using a different payer-accepted method that also accounted for differences between the FIDELIO-DKD and CREDENCE inclusion criteria and endpoints [3,4].