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Fast-rotating N=151 isotones 245Pu, 247Cm and 249Cf have been studied through inelastic excitation and transfer reactions with radioactive targets. While all have a ground-state band built on a νj15/2[734]9/2− Nilsson configuration, new excited bands have also been observed in each isotone. These odd-N excited bands allow a comparison of the alignment behavior for two different configurations, where the νj15/2 alignment is either blocked or allowed. The effect of higher order deformations is explored through cranking calculations, which help clarify the elusive nature of νj15/2 alignments. Keywords: Superheavy, Neutron-rich, Inelastic and transfer reactions, Rotational alignments, Higher-order deformations

Abstract Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D1033.32N (found only in the South-East Asian Region and Western Pacific Region) and T1945.42A (found only in South-East Asian Region), and 2 signalling SNVs (V1253.54A/T2526.36A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.

For over seven decades, dopamine receptor 2 (D2 receptor) antagonists remained the mainstay treatment for neuropsychiatric disorders. Although it is effective for treating hyperdopaminergic symptoms, it is often ineffective for treating negative and cognitive deficits. Trace amine-associated receptor 1 (TAAR1) is a novel, pharmacological target in the treatment of schizophrenia and other neuropsychiatric conditions. Several TAAR1 agonists are currently being developed and are in various stages of clinical and preclinical development. Previous efforts to identify TAAR1 agonists have been hampered by challenges in pharmacological characterisation, the absence of experimentally determined structures, and species-specific preferences in ligand binding and recognition. Further, poor insights into the functional selectivity of the receptor led to the characterisation of ligands with analogous signalling mechanisms. Such approaches limited the understanding of divergent receptor signalling and their potential clinical utility. Recent cryogenic electron microscopic (cryo-EM) structures of human and mouse TAAR1 (hTAAR1 and mTAAR1, respectively) in complex with agonists and G proteins have revealed detailed atomic insights into the binding pockets, binding interactions and binding modes of several agonists including endogenous trace amines (β-phenylethylamine, 3-Iodothyronamine), psychostimulants (amphetamine, methamphetamine), clinical compounds (ulotaront, ralmitaront) and repurposed drugs (fenoldopam). The in vitro screening of drug libraries has also led to the discovery of novel TAAR1 agonists (asenapine, guanabenz, guanfacine) which can be used in clinical trials or further developed to treat different neuropsychiatric conditions. Furthermore, an understanding of unappreciated signalling mechanisms (Gq, Gs/Gq) by TAAR1 agonists has come to light with the discovery of selective compounds to treat schizophrenia-like phenotypes. In this review, we discuss the emergence of structure-based approaches in the discovery of novel TAAR1 agonists through drug repurposing strategies and structure-guided designs. Additionally, we discuss the functional selectivity of TAAR1 signalling, which provides important clues for developing disorder-specific compounds.

BackgroundPresbycusis is characterized by sensorineural hearing loss in both ears at high frequencies, which affects more than half of the older adults by the age of 75 years and is often accompanied by tinnitus and cognitive deterioration. Unfortunately, there are no treatments available to restore hearing loss. Treatment mainly focuses on improving the quality of life and communication with hearing aids. Traditional medicine like Ayurveda also explains ailments of a similar nature as Badhirya and advises using drugs with antiaging and neuroprotective activity for treatment. In Ayurveda, Badhirya and Karnanada (senile deafness with tinnitus) are due to vitiation of Vata Dosha. Treatments such as topical oil pooling (Karnapurana) are usually advised to counter Vata, improve hearing capacity, and reduce tinnitus. Kshirabala Taila, a medicated oil formulation prepared with Sida cordifolia Linnaeus, is one of the most preferred oils for topical oil pooling in such conditions, as it has a definitive indication for sensory dysfunctions. Drugs like Withania somnifera (L.) Dunal (Ashwagandha) are also used, as they ameliorate neurodegeneration and help to improve cognitive dysfunction. ObjectiveWe propose an exploratory randomized controlled trial study for evaluating the efficacy of TOPMAC (Topical Oil Pooling with Kshirabala Taila and Supplementation of Ashwagandha Churna) in tinnitus suppression and hearing and cognitive function protection in patients aged 60-75 years with mild to moderate presbycusis. MethodsA parallel, 2-group, exploratory randomized controlled trial will be conducted in an Indian Ayurvedic research center at its outpatient service. Participants (N=60) with mild to moderate presbycusis will be recruited by screening. Participants will be randomized (computer-generated 1:1) to receive either basic treatment and health education (BTHE) or BTHE+TOPMAC for 24 weeks. The primary objective is to compare the efficacy of TOPMAC with that of BTHE in the protection of hearing function. The secondary objective is to compare the efficacy of TOPMAC with that of BTHE in tinnitus suppression and cognitive function protection. ResultsThis project was funded in January 2023. The institutional ethics committees at National Ayurveda Research Institute for Panchakarma (3/1/2020/NARIP/Tech/2036) and Institute for Communicative and Cognitive Neuro Sciences (IEC006) approved this study. The first patient was enrolled in September 2023; 22 participants were enrolled as of August 2024. The data analysis is yet to start, and the results are expected to be published by January 2025. ConclusionsIf this exploratory trial is proven effective, it will steer the setting of a definitive randomized controlled trial to test whether the TOPMAC intervention can be incorporated as a cost-effective integrative approach for managing presbycusis. The Indian government has already launched a National Program for Prevention and Control of Deafness to benefit the deaf population. TOPMAC may later be considered for integration with the national program. Trial RegistrationClinical Trials Registry India CTRI/2023/04/051485; https://tinyurl.com/2h2hry3n International Registered Report Identifier (IRRID)DERR1-10.2196/55089

Abstract Background and objective Non-alcoholic fatty liver disease (NAFLD) is primarily perceived as a condition prevalent among obese individuals. Its pathogenesis is closely intertwined with metabolic syndrome components. However, the association between insulin resistance and NAFLD in nonobese individuals remains ambiguous. Observational studies have scrutinized the prevalence of insulin resistance and metabolic syndrome in lean NAFLD patients. Materials and methods This is an observational study, and NAFLD screening was carried out among inpatient and outpatient attendees at SRM Medical College’s General Medicine Department. Out of 200 screened patients meeting inclusion and exclusion criteria, 80 were diagnosed with non-alcoholic fatty liver disease (NAFLD). The assessment of metabolic syndrome was performed using the NCEP-ATP III criteria, allowing for comparison between groups concerning insulin resistance and metabolic parameters. Results Among NAFLD patients, those in the obese age group exhibited a higher prevalence of hypertension (57.8%; p

Abstract Background Food insecurity and hunger are global concerns further exacerbated by the unprecedented COVID-19 pandemic. There is a need to understand the depth of this impact, especially among smallholder farmers, and recognize specific coping strategies that offered resilience to inform preparedness in future. The present cross-sectional study assessed the impact of the second wave of COVID-19 pandemic on different dimensions of food security among smallholder farmers of Ho indigenous community of Jharkhand, India. It also explored potential resilient attributes of their food systems. Results Most of the respondents (67.2%) reported reduced food consumption at the household (HH) level. Majority faced difficulty in accessing food from different food sources; however, easier access to government food security programmes was highlighted. Around 40% reported change in their ability to purchase farming inputs. Market vendors reported disruptions in food procurement owing to travel restrictions; however, no change was reported for home-produced foods in agricultural lands/kitchen gardens. Prices of indigenous foods produced locally decreased/remained same; however, for cereals, pulses, and other HH staples, prices increased during second wave. Difficulty in accessing wild food environment (OR: 1.7, CI 0.40, 7.75), change in food prices (OR: 19.9, CI 5.25, 76.02), decrease in HH income (OR: 9.2, CI 2.99, 28.60) were found to be significantly associated with reduction in HH food consumption (p

A suprasellar lesion is an unusual mass in the suprasellar region in the brain. Some common suprasellar lesions include Pituitary Adenoma, Craniopharyngioma and Meningioma. Patients may present with significant visual and other symptoms like headache, and hormonal imbalances. The proposed study utilizes 553 discharge summaries of suprasellar patients admitted during 2013–2019 at NIMHANS hospitals, Bangalore. Classification of discharge summary was conducted using 11 different word embedding techniques, including word2vec, FastText, Glove, and transformer-based embeddings. Tumor type is predicted using advanced ML classifiers like AdaBoost, Random Forest, and XGBoost. The highest F-score of 0.91 was reported for XGBoost when implemented along with SMOTE based data balancing and PCA based feature reduction. To enhance the classification performance of the best performing model, ClinicalBioBERT, a pre-trained BERT model that demonstrated superior results, was finetuned with domain-specific clinical data and resulted in an improvement of the F-score to 0.93. Classification of presence/absence of residual tumor post surgery is also carried out using transformer models and achieved a macro F1-score of maximum 1, after handling the class imbalance using SMOTE. Different combinations of experiments with PCA and SMOTE were carried out in both classification problems. Two Large Language Models: FlanT5 and Bloom, are also investigated in this work for both classification problems Initially, the LLM is employed with a zero-shot classification pipeline, resulting in poor performance. Consequently, fine-tuning of the LLM models are attempted using the discharge summary text, resulting in performance improvements.

The diagnosis of Multiple Myeloma (MM) is made by demonstration clonal plasma cells in Bone Marrow (BM) aspiration/biopsy, in addition to assessing serum biochemical parameters, conducting radiological examinations, and considering the clinical presentation. In most cases, predominantly mature plasma cells are observed, along with scattered immature forms in the BM. Several morphological variants of plasma cells have been reported, including Auer rod-like inclusions, small lymphocyte-like cells, hairy cell-like cells, anaplastic variants, promonocyte-like cells, crystal-storing histiocytes, Burkitt-like cells, and blastoid cells. In this series of five cases, most showed a typical clinical presentation and laboratory findings suggestive of plasma cell dyscrasia. However, the morphology of each case exhibited unusual morphological variants, posing diagnostic challenges. These variants included Auer rod-like inclusions, small lymphocytes/lymph-plasmacytoid cells, hairy-like cells, multilobulated nuclei, and anaplastic variants mimicking dysplastic megakaryocytes, leading to various differential diagnoses. The age range of these cases was 57-76 years. Most of the cases presented with generalised dull aching body pain. Imaging studies revealed lytic lesions involving various parts of the bone, including the skull, ribs, vertebrae, and femur. Biochemical assays suggested the possibility of plasma cell dyscrasia. Two of the cases had primary Plasma Cell Leukaemia (PCL), which is a rare and highly aggressive plasma cell neoplasm. The anaplastic variant is associated with a poor prognosis, aiding in predicting treatment responses. However, due to the unusual morphological presentation, the diagnosis of MM or PCL was made after conducting ancillary studies such as Serum Protein Electrophoresis (SPEP), serum free light chain assay, Immunofixation Electrophoresis (IFE), and immunophenotyping through Immunohistochemistry (IHC) or flow cytometry.

Background/Aims Rotational thromboelastometry (ROTEM) is a viscoelastic test that is used in patients with liver disease for guiding blood component use. This study is aimed at comparing the amount of blood products transfused and bleeding rates in patients without liver disease, who underwent therapeutic endoscopic procedures with deranged screening coagulation tests (prothrombin time [PT]; activated partial thromboplastin time [aPTT]), with and without hypocoagulable ROTEM.

Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

DC microgrids (DC MGs) offer advantages such as efficiency, control, cost, reliability, and size compared to AC MGs. However, they often operate with numerous constant power loads (CPLs), exhibiting a negative incremental impedance characteristic that can lead to instability. This instability weakens stability boundaries and reduces system damping, especially when dealing with pulsed power loads (PPLs) on electric aircraft, ships, and cars. Linear controllers may not ensure stability across various operations, causing voltage dips and potential system instability. To secure DC/DC converter functionality and comply with impedance specifications, it is crucial to consider minor loop gain in control strategies and stabilization techniques. Employing diverse methods to decrease minor loop gain in DC/DC converters is essential. A comprehensive evaluation, including strengths, weaknesses, opportunities, and threats (SWOT) analysis, is conducted to assess control strategies, stabilization techniques, and stability standards for different DC/DC converters, identifying SWOT.

The present study aims to propose an integrated watershed development plan for the Wainganga basin situated in Maharashtra, India. Also, the study involves evaluating the performance and applicability of SWAT (Soil and Water Assessment Tool) as a runoff model along with the trend analysis of rainfall for the above mentioned study area. The decadal land-use/land-cover (LULC) variation from 1985 to 2005 has been studied using data procured from Goddard Earth Sciences Data and Information Services Center (GES-DISC) and the groundwater table level of the study area was monitored using dug/bore well data collected from the Central Ground Water Board (CGWB). Rainfall trend analysis for a period of 101 years using historic rainfall data procured from the India Meteorological Department (IMD) has been analyzed to foresee the future scenario. It was observed that the rainfall-runoff relationship of the area is getting affected by the LULC variation and is thereby affecting the groundwater regime. There is a significant deterioration in the forest cover and water bodies which is alarming. The study devises the importance of an immediate master plan to be implemented in the basin to avoid any future crisis. Also, the study emphasizes the advancement of remote sensing in the use of hydrologic models like SWAT more realistically. HIGHLIGHTS The present study incorporates an integrated approach for watershed planning.; Rainfall runoff relationships were identified.; Land use-land cover anomalies and rainfall trend characteristics were analyzed.;

Context: A significant number of fine-needle aspiration cytology (FNAC) for thyroid nodules is reported as indeterminate. Expensive molecular testing can give a clue to the possibility of malignancy in this group. The effectiveness of serum thyroid-stimulating hormone (TSH) levels as a diagnostic tool in euthyroid patients with indeterminate cytology has not been previously studied, especially in the Indian population. Aims: This study was conducted to evaluate the predictive efficacy of serum TSH in the early diagnosis and treatment of malignancy. Settings and Design: This is a retrospective cross-sectional study on a cohort of patients who presented to our department with complaints of thyroid swelling and underwent thyroidectomy. Methods and Material: Euthyroid patients who underwent thyroid surgery for newly diagnosed thyroid nodules with FNAC reported as indeterminate cytology were included in our study. Based on the histopathological report, the patients were divided into two groups and into quartiles based on TSH values. Statistical Analysis Used: The mean difference in the numerical variables between groups was compared using the independent two-sample 't' test for parametric data and Mann–Whitney 'u' test for non-parametric data. A logistic regression analysis was done with age, sex, TSH level and nodule size as dependant variables and malignancy as the independent variable. Results: There were 211 patients in group A and 93 in group B. Patients with malignancy confirmed on final histopathology showed higher serum TSH levels compared to benign nodules (2.93 ± 1.067 vs 1.73 ± 1.051, P = 2.185 mIU/L). Conclusions: Serum TSH above 2.185 mIU/mL is a good predictor of malignancy in indeterminate nodules. It is an inexpensive, safe and reliable diagnostic screening test for the risk of malignancy in an indeterminate nodule.

The United Nations' Sustainable Development Goals (SDGs) explicitly acknowledge inclusive and equitable quality education as the primary goal of any global initiatives for early childhood development for children under 5 years with developmental delays and disabilities. Primary education provides the foundation for lifelong learning, vocational attainment, and economically independent living. Globally, the majority (over 90%) of children with developmental disabilities reside in low- and middle-income countries (LMICs). These children are significantly less likely to have foundational reading and numeracy skills, more likely to have never attended school and more likely to be out of primary school, compared to children without disabilities. Concerted and well-coordinated efforts to prepare these children in early childhood for inclusive education constitute a moral and ethical priority for all countries. This paper sets out to examine the concept and dimensions of school readiness for children under 5 years from an extensive narrative review of the literature. It identifies the barriers and challenges for school readiness for children with disabilities and the limitations of the available tools for evaluating school readiness. It concludes by emphasizing the critical role of inter-disciplinary engagement among pediatric caregivers in promoting school readiness in partnership with the families and community where the children reside. Overall, the paper highlights the need for appropriate policy initiatives at the global and national levels to promote school readiness specifically for children under 5 years with developmental disabilities in LMICs, if the aspirational goal of inclusive education by 2030 under the SDGs is to be realized.

AimThe provisions of the United Nation's Sustainable Development Goals (SDGs) for disability-inclusive education have stimulated a growing interest in ascertaining the prevalence of children with developmental disabilities globally. We aimed to systematically summarize the prevalence estimates of developmental disabilities in children and adolescents reported in systematic reviews and meta-analyses.MethodsFor this umbrella review we searched PubMed, Scopus, Embase, PsycINFO, and Cochrane Library for systematic reviews published in English between September 2015 and August 2022. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. We reported the proportion of the global prevalence estimates attributed to country income levels for specific developmental disabilities. Prevalence estimates for the selected disabilities were compared with those reported in the Global Burden of Disease (GBD) Study 2019.ResultsBased on our inclusion criteria, 10 systematic reviews reporting prevalence estimates for attention-deficit/hyperactivity disorder, autism spectrum disorder, cerebral palsy, developmental intellectual disability, epilepsy, hearing loss, vision loss and developmental dyslexia were selected from 3,456 identified articles. Global prevalence estimates were derived from cohorts in high-income countries in all cases except epilepsy and were calculated from nine to 56 countries. Sensory impairments were the most prevalent disabilities (approximately 13%) and cerebral palsy was the least prevalent disability (approximately 0.2–0.3%) based on the eligible reviews. Pooled estimates for geographical regions were available for vision loss and developmental dyslexia. All studies had a moderate to high risk of bias. GBD prevalence estimates were lower for all disabilities except cerebral palsy and intellectual disability.ConclusionAvailable estimates from systematic reviews and meta-analyses do not provide representative evidence on the global and regional prevalence of developmental disabilities among children and adolescents due to limited geographical coverage and substantial heterogeneity in methodology across studies. Population-based data for all regions using other approaches such as reported in the GBD Study are warranted to inform global health policy and intervention.

In this work, we present a new method—Thrombodynamics-4D—for the assessment of both plasma and platelet contributions to clotting. Thrombodynamics-4D potentially allows for the determination of plasma or platelet disorders and the effects of various drugs on plasma clotting or on platelet procoagulant function. In this assay, clot formation in platelet-rich plasma or platelet-free plasma supplemented with phospholipids is activated with tissue factor immobilized on a surface. Spatial fibrin clot growth and thrombin concentration dynamics are registered by measuring light scattering of the fibrin clot and fluorescence of the product formed by cleavage of the synthetic fluorogenic substrate by thrombin, respectively. Here, we describe the preanalytical requirements, measurement methodology and calculation principles of assay parameters. Preanalytical and analytical variability and reference ranges of the assay are given. Additionally, we show some clinical examples, which determine the effect of anticoagulants, measure clotting dysfunction in patients with platelet or coagulation disorders and evaluate the effect of surgery.

Marine electromagnetic (EM) signals largely depend on three factors: flow velocity, Earth's main magnetic field, and seawater's electrical conductivity (which depends on the local temperature and salinity). Because of this, there has been recent interest in using marine EM signals to monitor and study ocean circulation. Our study utilizes voltage data from retired seafloor telecommunication cables in the Pacific Ocean to examine whether such cables could be used to monitor circulation velocity or transport on large oceanic scales. We process the cable data to isolate the seasonal and monthly variations and then evaluate the correlation between the processed data and numerical predictions of the electric field induced by an estimate of ocean circulation. We find that the correlation between cable voltage data and numerical predictions strongly depends on both the strength and coherence of the model velocities flowing across the cable, the local EM environment, as well as the length of the cable. The cable within the Kuroshio Current had good correlation between data and predictions, whereas two of the cables in the Eastern Pacific Gyre – a region with both low flow speeds and interfering velocity directions across the cable – did not have any clear correlation between data and predictions. Meanwhile, a third cable also located in the Eastern Pacific Gyre showed good correlation between data and predictions – although the cable is very long and the speeds were low, it was located in a region of coherent flow velocity across the cable. While much improvement is needed before utilizing seafloor voltage cables to study and monitor oceanic circulation across wide regions, we believe that with additional work, the answer to the question of whether or not seafloor voltage cables can be used to study large-scale circulation may eventually be yes.

Abstract The quality of groundwater standards in Muttom–Mandaikkadu coastal stretch is the focus of the present study, whose coastal aquifers are particularly at risk due to intrusion of marine water. Thirty groundwater samples were scrutinized for the assessment of physical and chemical parameters during January and June. Hydrochemical characteristics were spatially depicted to understand the spatial variations such as (pH, EC, TDS, Na+, K+, Ca2+ and Mg2+, SO4 2−, HCO3−, and Cl−). Drinking water quality index based on those 11 parameters and irrigation water quality index based on EC, Na%, sodium adsorption ratio and permeability index was used to assess the water quality for drinking and irrigation, respectively. These results demonstrate that dominant hydrochemical facies for groundwater in both months are Na-K-Cl-SO4 type and Ca-Mg-Cl-SO4 type. The USSL diagram endorses that most of the water samples belong to low-medium salinity with low sodium hazards. Cl−/HCO3 − ratio indicates that the majority of the samples show low to moderate seawater intrusion in the study area. Additionally, six vertical electrical sounding measuring points (Schlumberger array) were carried out in order to determine the number of the underlying layers, aquifer depths and their thicknesses as well as its influence by the marine water. The geophysical self-potential measurements suggest that the groundwater in the Manavalakurichi area is prone to contamination by seawater intrusion, confirmed by the use of Schlumberger vertical electrical sounding. For better understanding, the subsurface layers were shown in a 2D model using the constructed geoelectrical cross section.

Context: Hemophilia A is classified as mild, moderate, and severe based on Factor VIII levels (FVIII). Clot-based assays only detect initiation of thrombin generation, hence FVIII levels may not accurately predict the bleeding risk in all hemophilia patients. The entire process of thrombin generation as measured by global hemostasis tests like activated partial thromboplastin time clot waveform analysis (APTT CWA) and thrombin generation test (TGT) may reflect the actual bleeding phenotype. Aims: To assess the utility of TGT and CWA as a screening tool to identify bleeders and to evaluate the bleeding phenotype in Hemophilia A. Settings and Design: Prospective, observational study of 147 consecutive patients referred for coagulation workup. Subjects and Methods: Bleeding assessment tool was used to identify bleeders. Patients were classified as severe and nonsevere bleeders based on clinical criteria. TGT was performed by calibrated automated thrombogram, CWA by photo-optical coagulometer and factor levels by one stage clot-based assays. Statistical Analysis Used: The Kruskal-Wallis test with post-hoc analysis was done to examine the difference in CWA/TGT parameters amongst hemophilia classified by FVIII levels. Receiver operating characteristic (ROC) analysis was performed to estimate the diagnostic accuracy of CWA and TGT in discriminating between clinically severe vs nonsevere bleeders. Results: Using ROC derived cut-offs of min1, min2 and peak height of thrombin (PH), the sensitivity (min1:91.67%, min2:91.67%, PH: 97.22%, FVIII: 86.11%) and specificity (min1:100%, min2:100%, PH: 90.91%, FVIII: 90.91%) of CWA/TGT was superior to FVIII to distinguish between clinically severe vs nonsevere bleeders. Phenotypic heterogeneity of bleeding severity was identified in our study population. Clinical severity correlated with CWA/TGT parameters instead of FVIII levels. Conclusions: CWA and TGT are more effective tools than conventional factor assays to identify clinically severe bleeders and tailor prophylaxis as per bleeding phenotype.

In a developing country like India, with limited resources and access to healthcare facilities, dealing with massive hemorrhage is a major challenge. This challenge gets compounded by pre-existing anemia, hemostatic disorders, and logistic issues of timely transfer of such patients from peripheral hospitals to centers with adequate resources and management expertise. Despite the awareness amongst healthcare providers regarding management modalities of bleeding patients, no uniform Patient Blood Management (PBM) or perioperative bleeding management protocols have been implemented in India, yet. In light of this, an interdisciplinary expert group came together, comprising of experts working in transfusion medicine, hematology, obstetrics, anesthesiology and intensive care, to review current practices in management of bleeding in Indian healthcare institutions and evaluating the feasibility of implementing uniform PBM guidelines. The specific intent was to perform a gap analysis between the ideal and the current status in terms of practices and resources. The expert group identified interdisciplinary education in PBM and bleeding management, bleeding history, viscoelastic and platelet function testing, and the implementation of validated, setting-specific bleeding management protocols (algorithms) as important tools in PBM and perioperative bleeding management. Here, trauma, major surgery, postpartum hemorrhage, cardiac and liver surgery are the most common clinical settings associated with massive blood loss. Accordingly, PBM should be implemented as a multidisciplinary and practically applicable concept in India in a timely manner in order to optimize the use the precious resource blood and to increase patients' safety.

Massive pulmonary hemorrhage during pulmonary thromboendarterectomy (PTE) can be managed by a conservative approach with mechanical ventilatory support, positive end-expiratory pressure, lung isolation, reversal of heparin, and correct of coagulopathy. We present three challenging cases that developed intrapulmonary hemorrhage during/after PTE and managed successfully. The first patient had bleeding from the bronchial artery and right internal mammary collaterals, which was managed by coil-embolization. The second patient had a breach in the blood airway barrier in the right upper lobar segment of the lung, and the repair was done using a surgical absorbable hemostat. The third patient developed reperfusion injury, he was instituted on veno-venous extracorporeal membranous oxygenation, a week later, the patient recovered completely. An algorithm was adopted and modified to our requirements; all the 3 challenging intrapulmonary hemorrhage cases were successfully managed. This algorithm can be used for satisfactory outcomes in patients who suffer intrapulmonary hemorrhage during PTE.

Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 > AD4 > Vina > RDOCK >> RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the S. aureus ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. campaigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking.