PLAS-20k: Extended Dataset of Protein-Ligand Affinities from MD Simulations for Machine Learning Applications.

Computing binding affinities is of great importance in drug discovery pipeline and its prediction using advanced machine learning methods still remains a major challenge as the existing datasets and models do not consider the dynamic features of protein-ligand interactions. To this end, we have developed PLAS-20k dataset, an extension of previously developed PLAS-5k, with 97,500 independent simulations on a total of 19,500 different protein-ligand complexes. Our results show good correlation with the available experimental values, performing better than docking scores. This holds true even for a subset of ligands that follows Lipinski's rule, and for diverse clusters of complex structures, thereby highlighting the importance of PLAS-20k dataset in developing new ML models. Along with this, our dataset is also beneficial in classifying strong and weak binders compared to docking. Further, OnionNet model has been retrained on PLAS-20k dataset and is provided as a baseline for the prediction of binding affinities. We believe that large-scale MD-based datasets along with trajectories will form new synergy, paving the way for accelerating drug discovery.

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma.

BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation. METHODS: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across myeloid subpopulations. Using 2 distinct murine glioma models, we examined the role of Trem2 on tumor progression and immune modulation of myeloid cells. Furthermore, we designed a method of tracking phagocytosis of glioma cells in vivo and employed in vitro assays to mechanistically understand the influence of TREM2 signaling on tumor uptake. RESULTS: We discovered that TREM2 expression does not correlate with immunosuppressive pathways, but rather showed strong a positive association with the canonical phagocytosis markers lysozyme (LYZ) and macrophage scavenger receptor (CD163) in gliomas. While Trem2 deficiency was found to be dispensable for gliomagenesis, Trem2+ myeloid cells display enhanced tumor uptake compared to Trem2- cells. Mechanistically, we demonstrate that TREM2 mediates phagocytosis via Syk signaling. CONCLUSIONS: These results indicate that TREM2 is not associated with immunosuppression in gliomas. Instead, TREM2 is an important regulator of phagocytosis that may be exploited as a potential therapeutic strategy for brain tumors.

Development of Automated Risk Stratification for Sporadic Odontogenic Keratocyst Whole Slide Images with an Attention-Based Image Sequence Analyzer.

(1) Background: The categorization of recurrent and non-recurrent odontogenic keratocyst is complex and challenging for both clinicians and pathologists. What sets this cyst apart is its aggressive nature and high likelihood of recurrence. Despite identifying various predictive clinical/radiological/histopathological parameters, clinicians still face difficulties in therapeutic management due to its inherent aggressive nature. This research aims to build a pipeline system that accurately detects recurring and non-recurring OKC. (2) Objective: To automate the risk stratification of OKCs as recurring or non-recurring based on whole slide images (WSIs) using an attention-based image sequence analyzer (ABISA). (3) Materials and methods: The presented architecture combines transformer-based self-attention mechanisms with sequential modeling using LSTM (long short-term memory) to predict the class label. This architecture leverages self-attention to capture spatial dependencies in image patches and LSTM to capture sequential dependencies across patches or frames, making it suitable for this image analysis. These two powerful combinations were integrated and applied on a custom dataset of 48 labeled WSIs (508 tiled images) generated from the highest zoom level WSI. (4) Results: The proposed ABISA algorithm attained 0.98, 1.0, and 0.98 testing accuracy, recall, and area under the curve, respectively, whereas VGG16, VGG19, and Inception V3, standard vision transformer attained testing accuracies of 0.80, 0.73, 0.82, 0.91, respectively. ABISA used 58% fewer trainable parameters than the standard vision transformer. (5) Conclusions: The proposed novel ABISA algorithm was integrated into a risk stratification pipeline to automate the detection of recurring OKC significantly faster, thus allowing the pathologist to define risk stratification faster.

Building Automation Pipeline for Diagnostic Classification of Sporadic Odontogenic Keratocysts and Non-Keratocysts Using Whole-Slide Images.

The microscopic diagnostic differentiation of odontogenic cysts from other cysts is intricate and may cause perplexity for both clinicians and pathologists. Of particular interest is the odontogenic keratocyst (OKC), a developmental cyst with unique histopathological and clinical characteristics. Nevertheless, what distinguishes this cyst is its aggressive nature and high tendency for recurrence. Clinicians encounter challenges in dealing with this frequently encountered jaw lesion, as there is no consensus on surgical treatment. Therefore, the accurate and early diagnosis of such cysts will benefit clinicians in terms of treatment management and spare subjects from the mental agony of suffering from aggressive OKCs, which impact their quality of life. The objective of this research is to develop an automated OKC diagnostic system that can function as a decision support tool for pathologists, whether they are working locally or remotely. This system will provide them with additional data and insights to enhance their decision-making abilities. This research aims to provide an automation pipeline to classify whole-slide images of OKCs and non-keratocysts (non-KCs: dentigerous and radicular cysts). OKC diagnosis and prognosis using the histopathological analysis of tissues using whole-slide images (WSIs) with a deep-learning approach is an emerging research area. WSIs have the unique advantage of magnifying tissues with high resolution without losing information. The contribution of this research is a novel, deep-learning-based, and efficient algorithm that reduces the trainable parameters and, in turn, the memory footprint. This is achieved using principal component analysis (PCA) and the ReliefF feature selection algorithm (ReliefF) in a convolutional neural network (CNN) named P-C-ReliefF. The proposed model reduces the trainable parameters compared to standard CNN, achieving 97% classification accuracy.

EEG-Based Cortical Alterations in Individuals With Chronic Knee Pain Secondary to Osteoarthritis: A Cross-sectional Investigation.

Chronic painful knee osteoarthritis (OA) is a disabling physical health condition. Alterations in brain responses to arthritic changes in the knee may explain persistent pain. This study investigated source localized, resting-state electroencephalography activity and functional connectivity in people with knee OA, compared to healthy controls. Adults aged 44 to 85 years with knee OA (n = 37) and healthy control (n = 39) were recruited. Resting-state electroencephalography was collected for 10 minutes and decomposed into infraslow frequency (ISF) to gamma frequency bands. Standard low-resolution electromagnetic brain tomography statistical nonparametric maps were conducted, current densities of regions of interest were compared between groups and correlation analyses were performed between electroencephalography (EEG) measures and clinical pain and functional outcomes in the knee OA group. Standard low-resolution electromagnetic brain tomography nonparametric maps revealed higher (P = .006) gamma band activity over the right insula (RIns) in the knee OA group. A significant (P < .0001) reduction in ISF band activity at the pregenual anterior cingulate cortex, whereas higher theta, alpha, beta, and gamma band activity at the dorsal anterior cingulate cortex, pregenual anterior cingulate cortex, the somatosensory cortex, and RIns in the knee OA group were identified. ISF activity of the dorsal anterior cingulate cortex was positively correlated with pain measures and psychological distress scores. Theta and alpha activity of RIns were negatively correlated with pain interference. In conclusion, aberrations in infraslow and faster frequency EEG oscillations at sensory discriminative, motivational-affective, and descending inhibitory cortical regions were demonstrated in people with chronic painful knee OA. Moreover, EEG oscillations were correlated with pain and functional outcome measures. PERSPECTIVE: This study confirms alterations in the rsEEG oscillations and its relationship with pain experience in people with knee OA. The study provides potential cortical targets and the EEG frequency bands for neuromodulatory interventions for managing chronic pain experience in knee OA.

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Mesenchymal Stem Cell Culture within Perfusion Bioreactors Incorporating 3D-Printed Scaffolds Enables Improved Extracellular Vesicle Yield with Preserved Bioactivity.

Extracellular vesicles (EVs) are implicated as promising therapeutics and drug delivery vehicles in various diseases. However, successful clinical translation will depend on the development of scalable biomanufacturing approaches, especially due to the documented low levels of intrinsic EV-associated cargo that may necessitate repeated doses to achieve clinical benefit in certain applications. Thus, here the effects of a 3D-printed scaffold-perfusion bioreactor system are assessed on the production and bioactivity of EVs secreted from bone marrow-derived mesenchymal stem cells (MSCs), a cell type widely implicated in generating EVs with therapeutic potential. The results indicate that perfusion bioreactor culture induces an ≈40-80-fold increase (depending on measurement method) in MSC EV production compared to conventional cell culture. Additionally, MSC EVs generated using the perfusion bioreactor system significantly improve wound healing in a diabetic mouse model, with increased CD31+ staining in wound bed tissue compared to animals treated with flask cell culture-generated MSC EVs. Overall, this study establishes a promising solution to a major EV translational bottleneck, with the capacity for tunability for specific applications and general improvement alongside advancements in 3D-printing technologies.

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Infraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders.

BACKGROUND: The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA ISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary objectives will be to examine patient-reported outcomes (PROs) and neurophysiological measures to (1) compare the potential effects of sham ISF-NFB to either genuine 1-region ISF-NFB or genuine 2-region ISF-NFB, and (2) assess for potential associations between changes in PRO scores and modifications of electroencephalographic (EEG) activity/connectivity within/between the trained regions of interest (ROIs). As part of an exploratory analysis, we will investigate the effects of additional training sessions and the potential for the potentiation of the effects over time. METHODS: We will randomly assign participants who meet the criteria for MDD, GAD, and/or SOC per the MINI (Mini International Neuropsychiatric Interview for DSM-5) to one of three groups: (1) 12 sessions of posterior cingulate cortex (PCC) ISF-NFB up-training (n=15), (2) 12 sessions of concurrent PCC ISF up-training and dorsal anterior cingulate cortex (dACC) ISF-NFB down-training (n=15), or (3) 6 sessions of yoked-sham training followed by 6 sessions genuine ISF-NFB (n=30). Transdiagnostic PROs (Hospital Anxiety and Depression Scale, HADS; Inventory of Depression and Anxiety Symptoms - Second Version, IDAS-II; Multidimensional Emotional Disorder Inventory, MEDI; Intolerance of Uncertainty Scale - Short Form, IUS-12; Repetitive Thinking Questionnaire, RTQ-10) as well as resting-state neurophysiological measures (full-band EEG and ECG) will be collected from all subjects during two baseline sessions (approximately 1 week apart) then at post 6 sessions, post 12 sessions, and follow-up (1 month later). We will employ Bayesian methods in R and advanced source-localisation software (i.e. exact low-resolution brain electromagnetic tomography; eLORETA) in our analysis. DISCUSSION: This protocol will outline the rationale and research methodology for a clinical pilot trial of sLORETA ISF-NFB targeting key nodes within the core-ICNs in a female ID population with the primary aims being to assess its potential efficacy via transdiagnostic PROs and relevant neurophysiological measures. TRIAL REGISTRATION: Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial ID: ACTRN12619001428156). Registered on October 15, 2019.

Acridine and Its Derivatives: Synthesis, Biological, and Anticorrosion Properties.

The phenomenon of corrosion threatens metallic components, human safety, and the economy. Despite being eco-friendly and promising as a corrosion inhibitor, acridine has not been explored to its full potential. In this review, we have discussed multiple biological activities that acridines have been found to show in a bid to prove that they are environmentally benign and much less toxic than many inhibitors. Some synthetic routes to acridines and substituted acridines have also been discussed. Thereafter, a multitude of acridines and substituted acridines as corrosion inhibitors of different metals and alloys in various corrosive media have been highlighted. A short mechanistic insight into how acridine-based compounds function as corrosion inhibitors have also been included. We believe this review will generate an impression that there is still much to learn about previously reported acridines. In the wake of recent surges to find efficient and non-toxic corrosion inhibitors, acridines and their analogs could be an appropriate answer.

PLAS-5k: Dataset of Protein-Ligand Affinities from Molecular Dynamics for Machine Learning Applications.

Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding affinity for a protein-ligand complex remains a major challenge. New datasets that allow for the development of models for predicting binding affinities better than the state-of-the-art scoring functions are important. For the first time, we have developed a dataset, PLAS-5k comprised of 5000 protein-ligand complexes chosen from PDB database. The dataset consists of binding affinities along with energy components like electrostatic, van der Waals, polar and non-polar solvation energy calculated from molecular dynamics simulations using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. The calculated binding affinities outperformed docking scores and showed a good correlation with the available experimental values. The availability of energy components may enable optimization of desired components during machine learning-based drug design. Further, OnionNet model has been retrained on PLAS-5k dataset and is provided as a baseline for the prediction of binding affinities.

Is There Evidence for the Specificity of Closed-Loop Brain Training in the Treatment of Internalizing Disorders? A Systematic Review.

Introduction: Internalizing disorders (IDs), e.g., major depressive disorder (MDD), posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) are the most prevalent psychopathologies experienced worldwide. Current first-line therapies (i.e., pharmacotherapy and/or psychotherapy) offer high failure rates, limited accessibility, and substantial side-effects. Electroencephalography (EEG) guided closed-loop brain training, also known as EEG-neurofeedback (EEG-NFB), is believed to be a safe and effective alternative, however, there is much debate in the field regarding the existence of specificity [i.e., clinical effects specific to the modulation of the targeted EEG variable(s)]. This review was undertaken to determine if there is evidence for EEG-NFB specificity in the treatment of IDs. Methods: We considered only randomized, double-blind, sham-controlled trials. Outcomes of interest included self/parent/teacher reports and clinician ratings of ID-related symptomatology. Results: Of the four reports (total participant number = 152) meeting our eligibility criteria, three had point estimates suggesting small to moderate effect sizes favoring genuine therapy over sham, however, due to small sample sizes, all 95% confidence intervals (CIs) were wide and spanned the null. The fourth trial had yet to post results as of the submission date of this review. The limited overall number of eligible reports (and participants), large degree of inter-trial heterogeneity, and restricted span of ID populations with published/posted outcome data (i.e., PTSD and OCD) precluded a quantitative synthesis. Discussion: The current literature suggests that EEG-NFB may induce specific effects in the treatment of some forms of IDs, however, the evidence is very limited. Ultimately, more randomized, double-blind, sham-controlled trials encompassing a wider array of ID populations are needed to determine the existence and, if present, degree of EEG-NFB specificity in the treatment of IDs. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], identifier [CRD42020159702].

Deep Learning-Based Microscopic Diagnosis of Odontogenic Keratocysts and Non-Keratocysts in Haematoxylin and Eosin-Stained Incisional Biopsies.

BACKGROUND: The goal of the study was to create a histopathology image classification automation system that could identify odontogenic keratocysts in hematoxylin and eosin-stained jaw cyst sections. METHODS: From 54 odontogenic keratocysts, 23 dentigerous cysts, and 20 radicular cysts, about 2657 microscopic pictures with 400× magnification were obtained. The images were annotated by a pathologist and categorized into epithelium, cystic lumen, and stroma of keratocysts and non-keratocysts. Preprocessing was performed in two steps; the first is data augmentation, as the Deep Learning techniques (DLT) improve their performance with increased data size. Secondly, the epithelial region was selected as the region of interest. RESULTS: Four experiments were conducted using the DLT. In the first, a pre-trained VGG16 was employed to classify after-image augmentation. In the second, DenseNet-169 was implemented for image classification on the augmented images. In the third, DenseNet-169 was trained on the two-step preprocessed images. In the last experiment, two and three results were averaged to obtain an accuracy of 93% on OKC and non-OKC images. CONCLUSIONS: The proposed algorithm may fit into the automation system of OKC and non-OKC diagnosis. Utmost care was taken in the manual process of image acquisition (minimum 28-30 images/slide at 40× magnification covering the entire stretch of epithelium and stromal component). Further, there is scope to improve the accuracy rate and make it human bias free by using a whole slide imaging scanner for image acquisition from slides.

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study.

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0-86.0) and 1.85 (0-37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5-13541.7) and 3708.0 (1311.0-14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0-364.0) and 122.4 (38.0-363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4-100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.

Evaluation of genotype by environment interaction and adaptability in lowland irrigated rice hybrids for grain yield under high temperature.

Recent predictions on climate change indicate that high temperature episodes are expected to impact rice production and productivity worldwide. The present investigation was undertaken to assess the yield stability of 72 rice hybrids and their parental lines across three temperature regimes over two consecutive dry seasons using the additive main effect and multiplicative interaction (AMMI), genotype and genotype × environment interaction (GGE) stability model analysis. The combined ANOVA revealed that genotype × environment interaction (GEI) were significant due to the linear component for most of the traits studied. The AMMI and GGE biplot explained 57.2% and 69% of the observed genotypic variation for grain yield, respectively. Spikelet fertility was the most affected yield contributing trait and in contrast, plant height and tiller numbers were the least affected traits. In case of spikelet fertility, grain yield and other yield contributing traits, male parent contributed towards heat tolerance of the hybrids compared to the female parent. The parental lines G74 (IR58025B), G83 (IR40750R), G85 (C20R) and hybrids [G21 (IR58025A × KMR3); G3 (APMS6A × KMR3); G57 (IR68897A × KMR3) and G41 (IR79156A × RPHR1005)] were the most stable across the environments for grain yield. They can be considered as potential genotypes for cultivation under high temperature stress after evaluating under multi location trials.

Clinical trials in otology: Examining trends and framework for prioritization.

OBJECTIVE: To characterize otologic clinical trials and examine otologic clinical trial trends from 2008 to 2018 using the clinicaltrials.gov database. METHODS: Data was collected from clinicaltrials.gov and included all clinical trials that focused on otology from 2008 to 2018. Outcome measures include status of trials, funding sources, details regarding otologic conditions studied, and trends in clinical trials. RESULTS: There were 992 otology clinical trials from 2008 to 2018.457 (46.1%) were completed and 94 (9.5%) were discontinued. Industry remained the highest (76.5%) contributor to otology clinical trials. The otologic conditions studied, from most common to least common, include hearing loss (40.6%), vestibulopathy (18.8%), tinnitus (18.8%), and otitis media (15.1%). The number of otology clinical trials increased by an average of 12.0 trials per year from 2008 to 2018 (p < 0.001). The number of otology clinical trials focusing on hearing loss and vestibulopathy significantly increased over the studied period (p < 0.001), while those focusing on tinnitus and otitis media did not (p = 0.09 and p = 0.20, respectively). The majority of clinical trials on each of these four conditions focused on treatment options. CONCLUSION: Our study describes trends in otology clinical trials registered on clinicaltrials.gov from 2008 through 2018. The total number of clinical trials over this time period increased significantly, driven by trials investigating hearing loss and vestibulopathy. Furthermore, most clinical trials were industry-sponsored and focused on treatment modalities. Our study provides an outline of otology clinical trials registered in a US web-based database, which may be of use for the development of future clinical trials.

Dipolar relaxation in thin films of supramolecular stacks of benzenecarboxamides and insights to enhance their ferroelectric characteristics.

The relationship between molecular structure and ferroelectric behaviour of thin films is explored in an all-organic supramolecular polymer material based on benzenecarboxamides, using atomistic molecular dynamics simulations. While increasing the number of amide groups around the phenyl core increases the dipole density of a molecule, increasing the length of the corresponding alkyl groups decreases the same. The interplay between these two contributions displays a rich behaviour on key material characteristics, in particular, the polarisation retention time. The latter is shown to be inversely proportional to the alkyl chain length, a consequence of weaker interactions between macrodipoles of stacks. Polarisation retention time was observed to be the highest in a molecule with five amide groups around the aromatic phenyl core which is explained as due to the large barrier for amide group rotation, which is one of the crucial channels for dipolar relaxation. Simulations also demonstrate that the barrier, however, does not affect the switchability of polarization, upon field reversal.

The Utility of Assessing Liver Allograft Fibrosis and Steatosis Post-Liver Transplantation Using Transient Elastography With Controlled Attenuation Parameter.

AIM: Allograft steatosis is an emerging concern after liver transplantation (LT). The use of transient elastography (TE) with controlled attenuation parameter (CAP) may facilitate early detection of and intervention for allograft steatosis. This study aimed to evaluate the prevalence and risk factors of allograft steatosis using TE and CAP. METHODS: The presence of steatosis and severe steatosis were defined by CAP ≥222 and ≥290 dB/m, respectively. Demographics and clinical characteristics were compared between patients with and without severe steatosis. Regression analyses were performed to determine factors associated with severe steatosis. RESULTS: Of 150 patients, 105 (70%) had steatosis while 40% of these had severe steatosis. Thirty-four (81.0%) patients with severe steatosis had normal alanine transaminase at the time of TE. In multivariable analyses, age at LT (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.08), post-LT obesity (OR 5.34, 95% CI 1.53-18.65), and alcoholic liver disease (OR 12.86, 95% CI 2.24-73.74) were significant predictors of severe steatosis. Five patients underwent liver biopsies as a result of advance fibrosis seen on TE and were later diagnosed with chronic allograft rejection. Two of these patients had normal liver chemistries, and the remaining 3 had mild elevation of alkaline phosphatase. CONCLUSION: Steatosis was present in 70% of patients who underwent TE after LT. Advanced age at LT, post-LT obesity, and alcoholic liver disease were significant predictors for severe steatosis. The majority of patients with severe steatosis had normal liver enzymes. TE should be considered as a screening modality for allograft steatosis and fibrosis even when liver chemistries are normal.